Autoimmune Infertility : Updates.

Immunologic processes can not only directly affect implantation and fertility, but they can also indirectly affect fertility through interfering with the endocrine system. There is a good deal of “crosstalk” between the hormonal system and the immune system. Reproductive processes depend on the interactions between cytokines and lymphokines, and hormones(9). When the female immune system is altered in function, as in autoimmune disease, the endocrine system can become affected, and fertility can be compromised. It is important to consider that autoimmune antibodies can develop sub-clinically many years before an actual symptomatic autoimmune disease is diagnosed, and during such time they may affect fertility(10).

It is quite clear that the immune system and endocrine system are connected. For example thyroid autoimmunity can result in hypothyroidism. Hypothyroidism can cause hyperprolactinemia which then may suppress ovulation. Thyroid antibodies have also been associated with endocrine disorders such as polycystic ovarian syndrome(11), and also with premature ovarian insufficiency(12) As another example of the link between the immune system on the endocrine system; SLE, Celiac disease, Endometriosis(13), and Type 1 diabetes have all been associated with hyperprolactinemia(14). Interestingly, extrapituitary immune sites can secrete prolactin, and this too has been associated with autoimmune disease. There is also evidence that there may be a silent form of autoimmune hypophysitis that can cause mild degrees of hormonal deficiencies(15). Such glandular autoimmunity may also involve the adrenals, ovaries, and even pancreas(16), all of which may have effects on reproduction.

The ovary itself has been described is an immunological hotspot(17). Immune dysfunction can adversely affect female fertility by prematurely diminishing ovarian reserve and increasing the speed of oocyte loss(18). Autoimmunity may also specifically impact androgen levels. It is well known that premature ovarian insufficiency(POI), a condition that affects 10% of all women, is associated with low levels of androgens(19). The adrenal glands produce 50% of all of the androgens, and 100% of the DHEA. Androgens are crucial for the early growing follicle maturation stages and when androgen levels are low, the follicles are held back from development.

An immune derived androgen-producing factor that acts on the adrenal glands and which may be functionally altered in patients with POI(20) may exist. A recent study found that in women with normal fertility, those with autoimmune activation tended to have higher levels of testosterone than controls(21), suggesting that a functional autoimmune androgen-producing factor (APF) may mediate the production of androgens. It was also found that women with POI had lower levels of testosterone than control women in the presence of the same immune activation, suggesting that this autoimmune regulatory function was altered.

In polycystic ovary syndrome, the most common reproductive disorder in women, this immunologic component may be important. Increased autoimmune activation through APF may be involved in the etiology of some androgenic phenotypes of PCOS(22). This information suggests that more research needs to be done on a possible ovarian-adrenal autoimmune system which could be involved in both POI and PCOS. It is important to note that functional autoantibodies can be either suppressive or enhancing.

Women with PCOS also have an increased incidence of a variety of serologic autoimmune markers, most especially Hashimoto’s thyroiditis(23). Polymorphisms related to inflammatory mediators IL-1 and Il6 are also more prevalent in PCOS, and CRP and IL18 levels are increased. It is difficult to determine however, if adjustments for obesity may remove these specific associations.