Study question: What is the long-term impact of controlled ovarian hyperstimulation (COH) on serum thyroid stimulating hormone (TSH) levels in euthyroid and hypothyroid women undergoing in vitro fertilization (IVF)? Summary answer: Three months after the end of COH, serum TSH concentration exceeds the recommended threshold of 2.5 mIU/L in one out of two adequately treated hypothyroid women and in one out of six euthyroid women. What is known already: It has been shown that in approximately one out of three euthyroid women and in two out of three hypothyroid women, TSH concentration exceeds the recommended threshold of 2.5 mIU/L during IVF cycles suggesting a reduced ability of the thyroid to adapt to the increased demand resulting from COH. However, whether thyroid function is restored at the end of the IVF cycle or whether COH results in a long-term impairment has not yet been investigated. Study design, size, duration: We selected women who underwent IVF and did not become pregnant. Cases were women with treated hypothyroidism and serum TSH <2.5 mIU/L prior to initiate the cycle. Controls were euthyroid women matched to cases by age (±1 year) and basal serum TSH ( ± 0.1 mIU/L). Participants/materials, setting, methods: Serum TSH was tested prior to initiate COH (Time 1), at the time of human chorionic gonadotropin (hCG) administration (Time 2), 16 days after hCG administration (Time 3) and three months after the end of the IVF cycle (Time 4). Thirty seven matched case-control pairs were selected. Main results and the role of chance: Serum TSH at Times 1, 2, 3 and 4 was 1.7 ± 0.6, 3.1 ± 1.4, 3.1 ± 1.3, 2.7 ± 1.7 mIU/L, respectively among cases and 1.7 ± 0.6, 2.9 ± 1.0, 2.7 ± 1.0, 1.9 ± 0.7 mIU/L, respectively among controls. A statistically signifi cant difference emerged at Time 4 (p < 0.001). In both groups, serum TSH was higher at time 4 compared to time 1. The rate of cases in which serum TSH exceeded the recommended threshold of 2.5 mIU/L at Time 4 was signifi cantly higher in cases (51%, 95% CI: 35–68%) compared to controls (16%, 95% CI: 4–28%) (p = 0.003). In the entire population the only predictive factor of TSH >2.5 mIU/L at Time 4 was a diagnosis of hypothyroidism (adjusted OR = 4.3, 95% CI: 1.1–17.7, p = 0.04). Limitations, reason for caution: Albeit unlikely, we cannot exclude that thyroid function may have deteriorated on its own (thus independently from COH) during the latency period of three months. Wider implications of the fi ndings: COH seems to have not only a short-term but also a long-term impact on TSH levels. The magnitude of this effect is particularly pronounced among hypothyroid patients. In a clinical perspective, we suggest to systematically retest thyroid function in women who underwent IVF few months after the end of COH, or in any case before a subsequent IVF cycle. Levothyroxine initiation or adjustment should then be considered in women overcoming the threshold of 2.5 mIU/L. Study funding/competing interest(s): Funding by hospital/clinic(s) – Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy. Trial registration number: NA. Keywords: thyroid, controlled ovarian hyperstimulation, TSH
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