SHBG as a Marker of NAFLD and Metabolic Impairments in Women Referred for Oligomenorrhea and/or Hirsutism and in Women With Sexual Dysfunction.

PCOS is one of the most common endocrine disorders and NAFLD is one of its most dangerous metabolic consequences. The diagnosis of NAFLD is not a practical task and the condition is at risk of being overlooked. The use of simpler but still reliable surrogate markers is necessary to identify women with a high likelihood of NAFLD. The aim of this study was to evaluate the clinical correlates of NAFLD Liver Fat Score (NAFLD-LFS) in women with oligomenorrhea and/or hirsutism. Furthermore, the study aimed to evaluate whether, among the hormonal parameters evaluated in such women, possible hallmarks of NAFLD may be identified. To this purpose, 66 women who attended our Outpatient Clinic for oligomenorrhea and/or hyperandrogenism were included in the study. In order to validate the results obtained in the first cohort, a second independent sample of 233 women evaluated for female sexual dysfunction (FSD) was analyzed. In cohort 1, NAFLD-LFS positively correlated with metabolic and inflammatory parameters. Among the hormone parameters, NAFLD-LFS showed no significant relationships with androgens but a significant negative correlation with SHBG (p<0.0001) that therefore appeared as a candidate hallmark for pathologic NAFLD-LFS. The ROC analysis showed a significant accuracy (81.1%, C.I.69.1-93.0, p <0.0001) for SHBG in identifying women with a pathological NAFLD-LFS. In particular, a SHBG 33.4 nmol/l was recognized as the best threshold, with a sensitivity of 73.3% and a specificity of 70.7%. In order to validate this SHBG as a marker of metabolic impairment possible related with the presence of NAFLD, we tested this threshold in cohort 2. FSD women with SHBG <33.4 nmol/l had worse metabolic parameters than women with SHBG ≥33.4 nmol/l and a significantly higher NAFLD-LFS even after adjusting for confounders (B=4.18 [2.05; 6.31], p=0.001). In conclusion, this study provides a new evidence in the diagnostic process of NAFLD, showing that the measurement of SHBG, which is routinely assessed in the workup of women referred for possible PCOS, could identify women at higher metabolic risk, thus detecting those who may deserve further targeted diagnostic assessment.

Insight on the Intracrinology of Menopause: Androgen Production within the Human Vagina.

In this study, we investigated steroidogenic gene mRNA expression in human vaginas and verified the ability of human vagina smooth muscle cells (hvSMCs) to synthesize androgens from upstream precursor dehydroepiandrosterone (DHEA). As a readout for androgen receptor (AR) activation, we evaluated the mRNA expression of various androgen-dependent markers. hvSMCs were isolated from vagina tissues of women undergoing surgery for benign gynecological diseases. In these cells, we evaluated mRNA expression of several steroidogenic enzymes and sex steroid receptors using real time reverse transcription-polymerase chain reaction. Androgen production was quantified with liquid chromatography tandem-mass spectrometry (LC-MS/MS). In vaginal tissues, AR mRNA was significantly less expressed than estrogen receptor α, whereas in hvSMCs, its mRNA expression was higher than progestin and both estrogen receptors. In hvSMCs and in vaginal tissue, when compared to ovaries, the mRNA expression of proandrogenic steroidogenic enzymes (HSD3ß1/ß2, HSD17ß3/ß5), along with 5α-reductase isoforms and sulfotransferase, resulted as being more abundant. In addition, enzymes involved in androgen inactivation were less expressed than in the ovaries. The LC-MS/MS analysis revealed that, in hvSMCs, short-term DHEA supplementation increased Δ4-androstenedione levels in spent medium, while increasing testosterone and DHT secretion after longer incubation. Finally, androgenic signaling activation was evaluated through AR-dependent marker mRNA expression, after DHEA and T stimulation. This study confirmed that the human vagina is an androgen-target organ with the ability to synthesize androgens, thus providing support for the use of androgens for local symptoms of genitourinary syndrome in menopause.

Nomegestrol acetate/17beta-estradiol does not negatively alter the vascular resistance of clitoral arteries: a prospective, exploratory study.

The effect of nomegestrol acetate/estradiol (NOMAC/E2) on clitoral and uterine vascularization has never been evaluated. We aimed to investigate, in women consulting for contraceptive needs, the possible changes in clitoral and uterine arteries hemodynamic parameters after 6 months treatment with NOMAC/E2 as compared with other hormonal contraceptives (HCs). In this observational, prospective pilot study, ten women were enrolled. Color Doppler ultrasound was performed on the clitoral and uterine arteries at baseline and after 6 months treatment with NOMAC/E2 (n = 5) or other HCs (n = 5). NOMAC/E2 did not exert any significant effect on clitoral vascular resistance expressed by the pulsatility index (PI); conversely, treatment with other HCs significantly increased this parameter (p = 0.04). The change in clitoral PI between the two groups retained a statistically significant difference even after adjusting for age. In the NOMAC/E2 group, at follow-up, uterine artery PI and acceleration were significantly reduced (p = 0.04), whereas no significant differences were observed in the HCs group; however, the change in uterine artery parameters did not differ significantly between the two groups. NOMAC/E2, differently from other COCs, does not negatively alter the vascular resistance of clitoral arteries and appears as a good contraceptive choice to protect both cardiovascular and sexual health.

Sexual Health in Menopause.

Sexual function worsens with advancing menopause status. The most frequently reported symptoms include low sexual desire (40-55%), poor lubrication (25-30%) and dyspareunia (12-45%), one of the complications of genitourinary syndrome of menopause (GSM). Declining levels of sex steroids (estrogens and androgens) play a major role in the impairment of sexual response; however, psychological and relational changes related with aging and an increase in metabolic and cardiovascular comorbidities should also be taken into account. Although first-line therapeutic strategies for menopause-related sexual dysfunction aim at addressing modifiable factors, many hormonal and non-hormonal, local and systemic treatment options are currently available. Treatment should be individualized, taking into account the severity of symptoms, potential adverse effects and personal preferences.

BRAF(V600E) assessment by pyrosequencing in fine needle aspirates of thyroid nodules with concurrent Hashimoto's thyroiditis is a reliable assay.

Detection of BRAF mutation in cytology specimens has been proposed as a diagnostic adjunctive tool in evaluation of thyroid nodules with indeterminate cytology findings. Concurrent papillary thyroid carcinoma and Hashimoto's thyroiditis (HT), a disease characterized by thyroid lymphocytic infiltration, is a frequent occurrence. A large lymphocytic infiltrate might reduce the sensitivity of methods employed to detect BRAF mutation in thyroid cytology specimens. To determine whether testing for BRAF mutational status in fine needle aspirates (FNA) is reliable also in the presence of HT lymphocytic infiltration, we assessed the BRAF status by direct sequencing and pyrosequencing in a series of FNAs with and without concomitant HT lymphocytic infiltration. We also performed the same assessment by pyrosequencing in the corresponding tissue samples. Pyrosequencing demonstrated to be more sensitive than direct sequencing. The percentage of mutant BRAF(V600E) alleles was higher in FNAs than in the corresponding tissues, probably because of the lower stromal contamination in FNA than in the sections. In the presence of lymphocytic infiltration, the percentage of mutant BRAF(V600E) alleles determined by pyrosequencing was higher in FNAs than in the corresponding tissue samples (P < 0.0001), indicating a minor lymphocytic contamination in FNA. The diagnostic value of BRAF(V600E) in inconclusive FNAs was not hampered by thyroid lymphocytic infiltration. These results indicate that BRAF(V600E) assessment by pyrosequencing is a reliable assay useful to refine inconclusive cytology of thyroid nodules also in the presence of concurrent HT.

BRAF mutation positive papillary thyroid carcinoma is less advanced when Hashimoto's thyroiditis lymphocytic infiltration is present.

BACKGROUND: Concomitant papillary thyroid cancer (PTC) and Hashimoto's thyroiditis (HT) is a frequent occurrence. Whether these two conditions are linked and whether PTC with concurrent HT has distinct clinicopathological characteristics are still debated issues. Lymphocytic infiltration is abundant in HT and might be relevant in the pathogenesis and progression of PTC. BRAF(V600E) mutation is associated with a more advanced PTC at diagnosis; however, its role in the clinicopathological characteristics of PTC with concurrent HT is unknown. DESIGN AND PATIENTS: We enrolled 146 patients with histological diagnosis of PTC. Microscopic assessment of histology samples was performed to identify the presence of lymphocytic infiltration. Detection of BRAF(V600E) was performed on cytology samples by both direct sequencing and pyrosequencing, and results were correlated with clinical parameters. RESULTS: Concurrent HT lymphocytic infiltration was associated with the female gender, smaller tumour size, a less frequent extracapsular extension and a lower grade of TNM staging. BRAF(V600E) was more frequent in PTC with concomitant lymphocytic infiltration. In PTC harbouring BRAF(V600E) , concurrent lymphocytic infiltration was still associated with the female gender, a less frequent extracapsular extension and a lower TNM staging. CONCLUSIONS: These results suggest that lymphocytic infiltration of HT is a protective factor against PTC progression, and it is independent of BRAF mutational status.

Metastatic renal cell carcinoma to the thyroid gland 24 years after the primary tumour.

Among the metastases to thyroid gland, metastases from renal cell carcinoma (RCC) are not rare and their frequent macroscopic looks are similar to primary thyroid tumours. We report an unusual case of thyroid metastases from renal carcinoma in a 72 -year-old man presented with a 1-year history of choking spells, stridor and dyspnoea. Patient underwent right nephrectomy for RCC, 24 years ago. In the present case, a right hemithyroidectomy was performed for a suspected anaplastic thyroid carcinoma. Histological examination showed a metastases of a clear cell renal carcinoma. Although the RCC showed an indolent biological behaviour, the late thyroid metastases have concurred with a poor prognosis and the patient died 5 months after surgery. The interest of this case lies in the long progression-free survival of the RCC preceded by the diagnosis of the thyroid nodule and the discrepancy between the clinical-radiological and the histological assessment.