Iodine and Fertility: Do we Know Enough?

Divya M. Mathews; Neil P. Johnson; Robert G. Sim; Susannah O'Sullivan; Jane M. Peart; Paul L. Hofman

Disclosures

Hum Reprod. 2021;36(2):265-274. 

In This Article

Insights From Animal Studies

There has been little research done in humans, but research in animal models studying the effect of iodine on uterus and ovaries has provided insight into the relationship between iodine and fertility.

Iodine-uterine Effects

Cows with UI showed improved fertility when treated with uterine instillation of Lugol's iodine. The authors postulated that infertility was secondary to subclinical endometritis and improvement could be due to potent bactericidal action of iodine to restore damaged endometrium. Other mechanisms suggested were changes in the uterine pH and improved uterine vascularity (Ahmed and Elsheikh, 2013, 2014).

Lipiodol was studied in rats to understand its effect in the uterus. Rats demonstrated alteration in the endometrial dendritic cell phenotype after Lipiodol instillation. Dendritic cells are important antigen presenting cells and may regulate establishment and maintenance of implanted embryo, which is foreign to the endometrium (Johnson et al., 2005). With each ml of Lipiodol having 480 mg of iodine, it is possible that iodine is the component in Lipiodol responsible for this immunological change in the uterine endometrium, improving implantation of the embryo. On the other hand, a large volume of iodine (50 ml) instilled into the uteri of mares resulted in severe edema and hemorrhage in the lamina propria with vacuolization, necrosis and blood vessel changes (van Dyk and Lange, 1986). This study suggests that large doses of iodine can be toxic while smaller doses such as that in the rat study may be beneficial in inducing a favorable uterine environment for normal reproduction.

Iodine-ovarian Effects

Iodine is essential for normal thyroid hormone synthesis and release and thereby indirectly promotes ovulation. Normal TSH promotes follicular growth in oocytes. TSH acts on the FSH receptors due to the structural similarity and enhances FSH induced pre antral follicular growth (Kobayashi et al., 2009).

In addition, iodine has direct action on the ovaries. Second only to the thyroid gland, ovaries have significant expression of the sodium-iodine symporter gene and this leads to iodine accumulation in ovaries after a large dose of iodine. The reason for the high ovarian iodine uptake remains largely unknown. However, studies done to understand the effect of radioactive iodine treatment on ovaries demonstrated that small and growing follicles take up more iodine and this appears to be crucial for ovarian granulosa cell secretory activities (Slebodziński, 2005). Iodine first accumulates in the walls of large Graafian follicles with maximal uptake by 4 h, followed by a shift to the follicular fluid. Estrogen can modify the iodine uptake by ovaries. Estradiol increases proliferation, but down-regulates the sodium-iodine symporter gene expression (Furlanetto et al., 1999).

Iodine deficiency, when artificially created in cows, resulted in anovulatory cycles. In contrast, pregnancy rates improved after adding iodine to their feeds, suggesting a causal-effect relationship between iodine and ovulation (Hidiroglou, 1979). Again, the optimal level of iodine is critical and excess iodine can have deleterious effects on ovaries as shown by Mahapatra and Chandra (2017) and Mahapatra et al. (2017) in murine studies. The iodine toxicity to ovaries was dose-dependent in their studies and associated with a negative fertility index. While 100-fold elevation of iodine levels produced hypoestrogenemia in rats, a 500-fold elevation resulted in hyperthyroxinemia and subsequent hyperestrogenemia, both situations negatively affecting fertility (Mahapatra and Chandra, 2017). These animal studies again point to an optimal iodine level necessary for normal ovarian reserve and reproductive function.

Iodine-immunological Effects

Successful pregnancy involves a complex interplay between immune cells and cytokines to promote or restrain inflammation at the maternal–fetal interface. An imbalance between Th17 (T helper cell), Treg (regulatory T cell) and NK cells (natural killer cell) can result in unexplained spontaneous recurrent abortions (Zhao et al., 2018). Dysregulated lymphocyte subsets and abnormal expression of cytokines were also found to be associated with recurrent implantation failure in women with chronic endometriosis (Wang et al., 2019). Iodine excess can alter the lymphocyte subset population as demonstrated by murine studies (Johnson et al., 2005; Yang et al., 2014; Saha et al., 2019). Murine studies examining the pathogenesis of autoimmune thyroiditis after an iodine load revealed that excess iodine upregulated Th17 cells, promoting inflammation. In addition, there was suppression of Treg cells (Yang et al., 2014). These studies suggest that iodine alters immunological milieu, potentially playing a role in embryo implantation. It is possible this could be detrimental to pregnancy length, with one population trial showing that each log-unit increase in serum iodide was associated with higher odds of preterm birth (Purdue-Smithe et al., 2019). Our literature review did not find any evidence to suggest increased or recurrent pregnancy losses with iodine excess. Similarly, there was no evidence that iodine deficiency seen at the levels in the current developed world resulted in increased pregnancy loss (Mills et al., 2019).

processing....