de Keyser, Catherine E.

Korevaar, Tim I.M.

English

EUR Research Repository

Controlled ovarianhyperstimulation as a stresstest for the thyroidThyroid hormone plays a relevant role in female reproduction.Thyroid hormone receptors are abundantly presentthroughout the female reproductive tract, and thyroid hor-mone regulates key processes in reproductive physiology,particularly through the downstream effects of follicle-stimulating hormone and luteinizing hormone (LH). From aclinical point of view, the role of thyroid hormone is reflectedby the consequence of thyroid disease. Hypothyroidism andhyperthyroidism are well-established modifiable risk factorsfor subfertility through the direct effects mentioned abovebut also through indirect effects, such as hyperprolactinemia,and alterations in gonadotropin-releasing hormone sensi-tivity and estradiol concentrations. The treatment indicationfor overt thyroid disease has been ubiquitously recognized,and recent studies have shown no benefit of levothyroxinetreatment for euthyroid thyroid autoimmunity (1). However,the benefit of levothyroxine treatment for milder forms ofthyroid disease, in particular subclinical hypothyroidism, re-mains unknown. This knowledge gap is frequently exploitedby fertility specialists to treat women with a normal thyroidfunction (i.e., a thyroid-stimulating hormone [TSH] concen-tration of >2.5 mU/L or even lower). Such nonevidence-based practices cause unnecessary psychosocial and biologicharm due to overdiagnosis and overtreatment.In the current issue, Busnelli et al. (2) report the resultsof their systematic review and meta-analysis assessing thy-roid function test changes throughout controlled ovarianhyperstimulation (COH). Studying these changes is espe-cially relevant because in this field, high-quality clinicalevidence is scarce and low-quality clinical data are oftenoverinterpreted. Therefore, future clinical studies or inter-ventions should be based on thyroid physiology ratherthan having a non-hypothesis-based approach. Experi-mental studies and studies on human physiology providea good basis for the current study. Low thyroid hormoneavailability is associated with suboptimal local ovarianstimulatory effects of follicle-stimulating hormone and LHbecause thyroid hormone regulates 3,b-hydroxysteroid de-hydrogenase (the final step in progesterone formation), aro-matase (the final step in estradiol formation), and LH/human chorionic gonadotropin receptor expression (3).Considering that COH is a state of supraphysiologic ovarianstimulation, this indicates that the identification of womenwith abnormal thyroid function test results that arise dur-ing COH may ultimately improve their outcomes. At thesame time, COH is a state of an increased demand for thy-roid hormone production. Although the thyroid functiontest results remain stable throughout a normal menstrualcycle, a rapid increase in the estradiol concentration duringCOH increases thyroxine-binding globulin concentrationsand type-3 deiodinase gene transcription (deactivating thy-roid hormone), leading to lower thyroid hormone availabil-ity and a subsequent increase in TSH concentration (3).VOL. 116 NO. 1 / JULY 2021After extracting data from 11 studies, the investigatorsshowed that in euthyroid women undergoing in vitro fertil-ization/intracytoplasmic sperm injection, the mean TSHconcentration increased by 0.69 mU/L (95% confidence in-terval [CI], 0.30–1.08) during COH, and this effect persisteduntil a positive pregnancy test result, whereas there waspractically no change in the mean free thyroxine (FT4) con-centration (0.34 pmol/L [95% CI, 0.91 to 0.23]) (2). Sub-analyses investigating women with thyroid autoimmunityrevealed highly heterogeneous results (effect estimatesranged between 0.1 to 2.86 mU/L), probably owing to thesmall number of women (n ¼ 7–24), suboptimal statisticalmodeling in the original studies, and combining thyroperox-idase antibody-positive women with thyroglobulinantibody-positive women (the latter are unlikely to presenta reduced thyroid functional capacity). Women with hypo-thyroidism treated with a fixed dose of levothyroxine werealso studied, which is relevant because in this group, thyroidfunction cannot be increased because of an increase in TSHconcentrations, making it a better controlled experiment. Inthese women, the mean TSH concentration increased by 1.50mU/L (95% CI, 1.10–1.89), which persisted for at least 3months after COH.This study provides the best quantitative data on the ef-fects of COH on thyroid function using a rigorous methodol-ogy and considers a longitudinal aspect with a baselinemeasurement that practically excludes reverse causality(2). It was not determined whether clinicians could havebased the type of COH on the thyroid function test outcome,which makes the results of analyses after stratification forthe different regimens difficult to interpret. The extent ofthyroid function changes, especially in hypothyroid womentreated with levothyroxine, indicates that COH is a state ofan increased demand for thyroid hormone production. The1.50 mU/L increase in the mean TSH concentration in thisgroup strengthens the recommendations of internationalguidelines to aim for a TSH treatment target of <2.5 mU/Lin women treated with levothyroxine before pregnancybecause this decreases the risk that relevant undertreatmentwill remain unidentified in between thyroid function assess-ments (4). Moreover, the minor increase in the TSH concen-tration among euthyroid women re-emphasizes that there isno basis at all for levothyroxine treatment in euthyroidwomen.This study also clearly exhibits that the quantity andquality of the currently available data is inadequate toidentify women at high risk of developing clinically mean-ingful thyroid function test abnormalities during COH thatwould require levothyroxine treatment (2). We certainlyagree with the investigators that future prospective studiesare required to identify subgroups with clinically meaning-ful thyroid function changes. An important limitation ofthis study is its design. An aggregate data meta-analysiscannot adequately deal with between-study differences instatistical methods, TSH/FT4 assays, and definitions of(ab)normal TSH, FT4, or thyroid antibody concentrations.This should be considered as a form of measurement errorthat can reduce the effect estimates toward the null.85REFLECTIONSTherefore, in parallel to new prospective studies, an indi-vidual participant data meta-analysis could provide rele-vant insights and can serve as a basis for the design offuture studies (5).Tim I.M. Korevaar, M.D. Ph.D.aCatherine E. de Keyser, M.D. Ph.D.ba Academic Center for Thyroid Disease, Department ofInternal Medicine, and b Vascular Medicine, Department ofInternal Medicine, Erasmus University Medical Center,Rotterdam, The Netherlandshttps://doi.org/10.1016/j.fertnstert.2021.04.025You can discuss this article with its authors and otherreaders athttps://www.fertstertdialog.com/posts/3292786REFERENCES1. Dhillon-Smith RK, Middleton LJ, Sunner KK, Cheed V, Baker K, Farrell-Carver S, et al. Levothyroxine in women with thyroid peroxidase antibodiesbefore conception. N Engl J Med 2019;380:1316–25.2. Busnelli A, Cirillo F, Levi-Setti PE. Thyroid function modifications in womenundergoing controlled ovarian hyperstimulation for IVF: a systematic reviewand meta-analysis. Fertil Steril 2021;116:218–31.3. Korevaar TI. Thyroid disorders during preconception, pregnancy, and thepostpartum period. In: Werner and Ingbar's. The thyroid, 11. Philadelphia,PA: Wolters Kluwer; 2020.4. Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al.Guidelines of the American Thyroid Association for the diagnosis and man-agement of thyroid disease during pregnancy and the postpartum. Thyroid2017;27:315–89.5. Korevaar TI, Derakhshan A, Taylor PN, Meima M, Chen L, Bliddal S, et al. As-sociation of thyroid function test abnormalities and thyroid autoimmunitywith preterm birth: a systematic review and meta-analysis. JAMA 2019;322:632–41.VOL. 116 NO. 1 / JULY 2021

Controlled ovarian hyperstimulation as a stress test for the thyroid

https://pure.eur.nl/files/36895139/Controlled_ovarian_hyperstimulation_as_a_stress_test_for_the_thyroid.pdf

Controlled ovarian hyperstimulation as a stress test for the thyroid

Abstract

Similar works

Full text

Available Versions

EUR Research Repository

EUR Research Repository