An interesting observation pertinent to
An interesting observation pertinent to the immunology of pregnancy comes from a study by Kruse et al., they found that recurrent miscarriage patients with higher serum progesterone levels had lower Th1/Th2 cytokine ratios suggesting that progesterone levels modulate cytokine production patterns. Progesterone has also been shown by Piccinni et al. to preferentially support the development of human T insulin receptor producing Th2 cytokines in vitro; they contend that Th2 cytokines may promote allograft tolerance and foetal survival.
Clinical applications of progesterone and dydrogesterone A recent Cochrane review has shown progesterone supplementation to reduce miscarriage rates without any adverse effects. A systematic review of progesterone supplementation in RSM has shown a significant beneficial effect. Similarly progestogen supplementation has been reported to reduce the rate of threatened abortion. Therefore, patients who have had a prior spontaneous miscarriage may well benefit from progesterone therapy. Hill et al. have proposed that progesterone, referred to as “nature's immunosuppressant”, may benefit women in whom the aetiology of RSM is related to maternal Th1 cytokine predominance. Despite the promise that progesterone supplementation holds out, it should be pointed out that progesterone administered orally is poorly absorbed, is subject to first-pass mechanism, has a short biologic half-life, loses much of its bioactivity and is cleared rapidly. On the contrary, the orally-active progestogen dydrogesterone is superior from this perspective, as it does not suffer from these drawbacks; as mentioned above, we have shown that dydrogesterone retains immunomodulatory activity even after it is converted to its major metabolite after oral administration. El-Zibdeh reported that dydrogesterone-treated women with unexplained RSM had fewer miscarriages compared to placebo controls. Therapy with dydrogesterone in threatened abortion led to a significantly higher rate of continuing pregnancy success. An impressive randomized, double-blind, placebo-controlled study on dydrogesterone supplementation by Kumar et al. recently demonstrated a significant decrease in the number of miscarriages as well as an increase in the mean gestational age at delivery. Based on a systematic review of randomized trials on dydrogesterone, Carp concluded that supplementation with dydrogesterone results in a 13% absolute reduction in the miscarriage rate, with minimal side-effects. The results of this systematic review demonstrate a significant reduction of 29% in the odds for miscarriage when dydrogesterone is compared to standard care, indicating a real treatment effect.
Concluding perspectives The observations summarized in this review demonstrate that dydrogesterone, a progestogen that is currently indicated for progesterone-related pregnancy disorders from an “endocrinologic” perspective, has immunomodulatory capability as well. It is able to induce a maternal cytokine shift from Th1 or pro-inflammatory cytokine dominance towards a Th2 or anti-inflammatory bias, a profile that appears to be favourable to the success of pregnancy. Thus, progestogens may well find use for effective, safe and orally-administered therapeutic intervention in unexplained recurrent spontaneous miscarriage. It is possible that the assessment of individualized “personal cytokine profiles” in women with pregnancy complications may point to an immunologic aetiology. This could then be followed by modulation of cytokine profiles by therapeutic supplementation with progestogens as indicated by the personal cytokine profile of each patient. Oral dydrogesterone has been shown to be more effective than micronized vaginal progesterone in luteal phase support. Chakravarty et al. have reported that while treatment with dydrogesterone and micronized progesterone yielded similar rates of successful pregnancies, dydrogesterone had a higher tolerability by patients. The well-established safety profile of dydrogesterone and the fact that it is administered orally make it an attractive candidate for immunomodulation in pregnancy complications.