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J Assist Reprod Genet. 2015 Dec;32(12):1765-72. doi: 10.1007/s10815-015-0588-x. Epub 2015 Oct 14.

Acute immunomodulatory changes during controlled ovarian stimulation: evidence from the first trial investigating the short-term effects of estradiol on biomarkers and B cells involved in autoimmunity.

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Division of Rheumatology, Department of Medicine, University of Padua, Padua, Italy.
Department of Woman and Child Health, Gynaecologic and Obstetric Unit, University of Padua, Padua, Italy.
Dipartimento di Salute della Donna e del Bambino, U.O.C. di Ginecologia e Ostetricia, Via Giustiniani 3, 35128, Padova, Italy.
Department of Woman and Child Health, Gynaecologic and Obstetric Unit, University of Padua, Padua, Italy.
Department of Obstetrics and Gynaecology, University of Verona, Verona, Italy.
Department of Laboratory Medicine, University of Padua, Padua, Italy.



The aim of the present study was to evaluate the in vivo immunomodulatory effects of an acute short-term estradiol (E(2)) increase on serum levels of B cell-activating factor (BAFF), immunoglobulins (Ig), anti-nuclear antibodies (ANA), and the peripheral B cell phenotype.


We conducted, at the Infertility Center of the University of Padua, a prospective case-control study on a cohort of infertile normo-responder women (group-A, 63 patients) undergoing controlled ovarian stimulation (COS) compared with an age-matched cohort of normo-ovulatory healthy women (group-B, 39 patients). Three serial blood sample assays were conducted in both groups, at T0, hypothalamic suppression; T1, ovulation induction; and T2, βhCG test in group A, and at T0, 2nd day; T1, 14th day; and T2, 21st day of cycle in group B, and serum levels of E(2) and BAFF, BAFF/E(2) ratio, circulating IgM, IgG, and IgA, ANA titer, and peripheral B cell phenotype were measured. We compared group-A versus group-B in terms of absolute and E(2) normalized values of BAFF at baseline (T0) to verify for possible differences between healthy and infertile women, at T1 to verify for possible differences occurring after spontaneous ovulation versus COS, and at T2 to evaluate differences in serum BAFF levels between pregnant versus non-pregnant patients (considering only group-A) and between non-pregnant women after spontaneous versus COS cycles (group-B versus group-A). In group-A, we also evaluated IgM, IgG, IgA levels, ANA titer, and peripheral B cell phenotype at T0 versus T1 versus T2.


With the exception of E(2) levels at T1 (as expected), no significant differences were found between the two groups for all outcome measures. In group-A, BAFF at T0 positively correlated with IgM levels; marginal zone CD19+/CD27+/IgD+ memory B cell compartment tended to be expanded at T1 when compared with T0.


Despite several mechanistic and clinical studies supporting a stimulatory role of E(2) on autoimmunity, the acute increase of E(2) during COS for infertility treatment does not seem to have a major impact on the immune system.


Acute immunomodulation; Autoimmunity biomarkers; BAFF; BLyS; Controlled ovarian stimulation; IVF; Memory B cells; Short-term estradiol increase

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