Flaminia Fanelli (Presenter)
University of Bologna - S.Orsola-Malpighi Hospital
Bio: Flaminia Fanelli is a medical biotechnologist with a PhD in Experimental and Clinical Medical Sciences. She has 10 years experience in LC-MS/MS assay development, methods’ comparison and clinical validation studies. As leader of the analytical division of the Endocrinology Unit, she’s been contributing to conception and management of several analytical and clinical studies, developing relevant skills in team organization and multidisciplinary collaborations. Dr. Fanelli contributed to national (PRUa g.a. n°1a-2007-006, n°1-2012-004; PRIN 2010-2011: AMLET) and EU (g.a. n°22371, n°279171, n°245009, n°613979) funded studies involving LC-MS/MS metabolite and hormone profiling in human (serum and saliva), animal and in vitro fluids in obesity, sex hormone imbalance and steroidogenesis deficits. She has several Italian and International collaborations.
Authorship: F. Fanelli, M. Mezzullo, L. Zanotti, A. Fazzini, U. Pagotto, R. Pasquali, A. Gambineri
Endocrinology Unit and Center for Applied Biomedical Research, Department of Medical and Surgical Sciences, University of Bologna - S.Orsola-Malpighi Hospital
Hirsutism and hyperandrogenemia are indistinctly used to assess hyperandrogenism in the diagnosis of polycystic ovary syndrome (PCOS), however, recent studies suggest that they have different hormonal and metabolic correlates. LC-MS/MS multianalyte potential was used to characterize steroid profile in hirsute vs not hirsute women characterized by different combination of hyperandrogenemia and ovarian dysfunction. While idiopathic hirsutism did not show relevant alteration of the steroid profile and of enzyme activity pattern, hirsute PCOS women displayed an increased P450 activity and a less severe androgen profile compared to PCOS not hirsute counterparts, combined with a less active gonad secretion and with a higher activity of the glucocorticoid pathway. Our results overall suggest an involvement of the adrenal in the hirsute PCOS phenotype.
Hirsutism (HIR) and hyperandrogenemia (HA) are currently indistinctly used to assess hyperandrogenism in the diagnosis of polycystic ovary syndrome (PCOS), however, recent studies suggest that they have different hormonal and metabolic correlates. In addition, hirsute women often present normal circulating androgen levels as assayed by direct routine immunoassays (IAs). The lack of overlap between hirsutism and HA could be due to the synthesis of active androgens at the pilosebaceous unit, as well as to the poor reliability and to the limited panel of steroids measurable by routine IAs. LC-MS/MS is renewing steroidology by providing highly sensitive and accurate measurements of large steroid panels. This study aimed at characterizing the steroid profile of the hirsute phenotype within the heterogeneous PCOS context.
HIR (modified Ferriman-Gallway score ≥8), HA (TLCMSMS≥0.45 ng/ml; FAI≥1.80 and ≥0.62 in lean and overweight/obese women, respectively) and ovarian dysfunction (OD; oligo-amenorrhea and/or PCO morphology) were assessed in 352 women attending the Bologna Endocrinology Unit. Women were grouped according to HA and OD combinations in: i) no OD + no HA (not-HIR, n=69 ; HIR, n=36); ii) OD + no HA (not-HIR, n=54; HIR, n=59); iii) HA + no OD (not-HIR, n=17; HIR, n=14 ); iv) HA + OD (not-HIR, n=38; HIR, n=65). Anthropometric data were registered. Blood was taken in follicular phase after an overnight fast. Routine metabolic and hormonal parameters were measured. Fifteen serum steroids among estrogens, androgens, glucocorticoid and precursors were determined by two in-house LC-MS/MS assays; product/substrate ratios were calculated for enzymatic activity estimation.
HIR women in OD + no HA group and HIR women in OD + HA group displayed higher BMI and a worse metabolic profile in terms of dyslipidemia and insulin resistance, respectively. Steroid profiling revealed lower progesterone level in HIR vs not-HIR women in OD + no HA group (P<0.001) and less elevated 17OHprogesterone, androstenedione and testosterone in HIR vs not-HIR OD + HA women (P=0.006, P=0.020 and P=0.001, respectively).
Product / precursor ratio overall showed a higher P450c17 activity in HIR vs not-HIR women in OD + no HA group (17OH-Progesterone/Progesterone: P=0.013; DHEA/17OH-Pregnenolone: P=0.028; Androstenedione/17OH-Progesterone: P<0.001); a lower 3β-HSD2 activity and a higher P450c21 activity in HIR vs not-HIR women in the HA + no OD group (Androstenedione/DHEA: P=0.016; 11deoxycortisol/17OH-Progesterone: P=0.018), a lower 3 β -HSD2 activity in HIR vs not-HIR women in the HA + OD group (Androstenedione/DHEA: P=0.015). HIR women in the No OD + No HA group did not show any difference in steroid levels and ratios in respect to not-HIR counterparts.
Conclusions & Discussion
By using a broad LC-MS/MS profiling in the complex frame of PCOS, we found that hirsute women have a different steroid pattern as compared to not hirsute women, overall characterized by less a severe hyperandrogenemia, by a lower gonad secretion and by increased adrenal involvement. The more active glucocorticoid pattern observed in hirsute women could explain their worse metabolic profile. Finally, Idiopathic hirsutism seems to be due to a local phenomenon at the pilosebaceous unit.
References & Acknowledgements:
This work was supported by the of Emilia-Romagna Region – University Program, Alessandro Liberati Young Researcher Grants, PRUA 1-2012-004.
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