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AJR 2004; 183:1725-1727
© American Roentgen Ray Society

Opinion

Enhanced Fertility After Diagnostic Hysterosalpingography Using Oil-Based Contrast Agents May Be Attributable to Immunomodulation

Anthony J. Yun1 and Patrick Y. Lee

1 Both authors: Department of Radiology, Stanford University, 470 University Ave., Palo Alto, CA 94301.

Received April 8, 2004; accepted after revision April 23, 2004.

 
Address correspondence to A. J. Yun (ayun{at}stanford.edu).

For decades, diagnostic hysterosalpingography (HSG) performed with Ethiodol (ethiodized poppy seed oil, Savage Laboratories) has been recognized as having therapeutic value in infertile women. A 1971 retrospective analysis of the rates of conception occurring within 1 year of the termination of infertility treatment showed that more women conceived after HSG with Ethiodol than after HSG with water-soluble agents (55% vs 40%), whereas 43% of those who did not undergo HSG conceived [1]. In 1983, a randomized prospective trial revealed that subgroups of women with infertility of unknown cause were more likely to become pregnant within the four menstrual cycles after HSG with an oil-soluble contrast agent than after HSG with a water-soluble agent [2]. A 1991 randomized prospective trial involving 398 patients with infertility similarly showed that women who underwent HSG with ethiodized poppy seed oil (Ethiodol) were more likely both to become pregnant and to carry full-term than those who underwent HSG with any water-soluble agent [3]. A meta-analysis of four randomized and six nonrandomized trials evaluating pregnancy rates after HSG using an oil- or water-soluble contrast agent showed the therapeutic benefit of oil-soluble agents [4]. The phenomenon is sometimes attributed to mechanical or lubricating effects of the contrast agent, but no explanatory mechanism is generally accepted.

To explain the HSG–fertility phenomenon, we offer an alternative biologic hypothesis based on emerging basic scientific data from reproductive immunology. We propose that immunomodulation by oil-soluble agents may enhance fertility. Specifically, we postulate that oil-soluble agents contain constituents that can shift endometrial immune balance towards T-helper type 2 (Th2) bias, a state more favorable for successful implantation and gestation.

The important role played by the appropriate Th immune balance for fertility in the female reproductive tract is being increasingly recognized. From the maternal perspective, gestation is a balancing act between host defense against infection and immune tolerance of the fetal allograft [5]. Emerging evidence suggests that this balance may be achieved by oscillating the Th1–Th2 balance during the menstrual cycle, with a shift to relative Th2 bias after ovulation [6]. Broadly speaking, Th1 cells drive cell-mediated immunity by producing cytokines such as interleukin-2 (IL-2) and interferon-{gamma}, whereas Th2 cells drive humoral immunity by producing cytokines such as IL-4, IL-5, and IL-10 [7]. The Th2 bias of the luteal phase is thought to be an adaptation to reduce the risk of Th1-mediated rejection of the zygotic allograft and gametes [8].

Indeed, recent data suggest that Th1-type cytokines drive allograft rejection and compromise pregnancy, whereas Th2-type cytokines promote allograft tolerance and dampen Th1 immunity [9]. Compared with the peripheral circulation, the decidua contains far more Th2-type cells [10], and the decidua has been found to secrete more Th2 cytokines such as IL-4 and IL-10 during early pregnancy than is contained in the peripheral blood [11]. Leukemia inhibitory factor (LIF), which is considered essential for embryo implantation, is up-regulated by IL-4 and progesterone and down-regulated by Th1 inducers such as IL-12 and interferon-{gamma} [12]. IL-4 and LIF are constitutively expressed in vivo by the cumulus oophorus, a mass of cells surrounding the oocyte, whereas interferon-{gamma} is not [13]. Interferon-{gamma} has been shown to alter various plasma membrane domains and cytoskeletal organization in early-stage embryos [14]. These findings support the notion that Th2 bias in the uterine microenvironment may be vital for successful implantation.

Various clinical studies have confirmed that an inappropriate Th1–Th2 balance causes subfertility [15]. Deficient secretion of Th2 cytokines such as LIF, IL-4, and IL-10 by decidual T cells correlates with recurrent spontaneous abortions [16]. Diminished populations of Th2 cells at the implantation site are associated with pregnancy failure [17]. Enhanced Th1 activity is seen in women with recurrent pregnancy loss and implantation failures [18–20]. Assessment of in vivo periimplantation cytokines in the endometrial lining showed that, independent of hormonal factors, women with recurrent miscarriages exhibit primarily Th1 cytokines, whereas women with normal pregnancies exhibit decreased Th1 cytokines and increased Th2 cytokines [21].

In this context, the potential immunomodulatory properties of ethiodized poppy seed oil are intriguing. Poppy seed oil is composed of various chemical entities including a large fraction of linoleic acid (C18H32O2), a polyunsaturated fatty acid of the {omega}-6 series [22]. Linoleic acid is a component of both fish oils, which are generally high in (n-3) polyunsaturated fatty acids, and vegetable oils, which are generally high in (n-6) polyunsaturated fatty acids [23]. Laboratory studies have shown that polyunsaturated fatty acids shift the immune balance toward Th2 bias by depleting Th1 function [24]. The (n-3) polyunsaturated fatty acids have been shown to attenuate T cell–mediated immunity, a Th1 function, in humans and experimental model systems, and the (n-6) polyunsaturated fatty acids have been shown to promote inflammation, a Th2 function [25–27]. Other studies have shown that polyunsaturated fatty acids reduce IL-2 production, increase T cell apoptosis, and activate IL-4-driven Th2 cells [28–30]. Polyunsaturated fatty acids are thought to promote apoptosis of Th1 cells (but not of Th2 cells) possibly through up-regulation of fatty acid synthase (Fas) and Fas ligand [31–33]. Collectively, these studies support the notion that the poppy seed oil in Ethiodol may have immunomodulatory properties that shift the Th balance toward a Th2 bias.

We hypothesize that Ethiodol may promote fertility through modulation of Th balance toward a Th2 bias in the female reproductive tract, a condition that may facilitate host immune evasion by the gametes and the fetal allograft. More than three decades of clinical experience, including multiple randomized clinical trials, have established empiric evidence of fertility benefits using ethiodized poppy seed oil in HSG. The emerging scientific evidence in the immunology, reproductive biology, and lipid biology literature is pointing to a potential novel biologic explanation for this phenomenon. We are not aware of any study to date that has investigated directly the ability of ethiodized poppy seed oil to modulate Th balance in the endometrial environment. Such a study, along with a correlation study mapping the altered Th balance after Ethiodol administration with enhanced fertility, would help validate our hypothesis of this mechanism. Potential undesirable effects of Ethiodol-induced Th2 inflammation in the reproductive tract should also be further researched. Elucidating the mechanism of fertility benefit could yield refinements of current HSG techniques and may open the door for future molecular imaging and therapeutic approaches to managing patients with infertility.


References
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