A common problem for many of our IVF patients is diminished ovarian reserve (DOR). This happens naturally as we get older but unfortunately, can also occur at earlier ages in some women. When a patient has DOR, she will typically have a higher Follicle Stimulating Hormone (FSH) level, a low Anti-Mullerian Hormone (AMH) level or low numbers of antral (small) ovarian follicles. She may have just one or two of these findings, or all of them. Not untypically, women with this problem will require large doses of injectable ovarian stimulating fertility medications to achieve a reasonable response to do IVF (e.g. four or more mature follicles).
Ever since IVF was first invented, it became clear that some women will have a less than desirable response to ovarian stimulation. Consequently, reproductive endocrinologists have always been interested in trying to determine whether or not there are any medications or supplements that might enhance the responses of poorly responding patients. This has led to the common use of four substances I will discuss in this article: the adrenal hormone DHEA (de-hydro-epi-androsterone), testosterone, the vitamin supplement Co-enzyme Q10 (CoQ10) and human growth hormone (hGH). Many women with a history of DOR, prior poor responses and/or poor quality embryos are advised to use these supplements to their fertility therapy and I would like to cover the rationale behind these recommendations and review the existing data to support their use.
DHEA and testosterone are weak and potent androgens (male hormones) respectively. Women make DHEA in the adrenal gland and it is converted in various tissues to testosterone. Women also make small amounts of testosterone in the ovaries. Some observations that have led to the idea that androgens might improve the response to FSH (and therefore the responses to the fertility medications Follistim and Gonal-f) include the fact that women with polycystic ovarian syndrome (PCOS) have both high androgen levels, lots of follicles and are high-responders to fertility medications. Also, it has been reported that the majority of female to male transsexuals being treated with high doses of testosterone tend to develop PCOS-like ovaries.
DHEA was studied because it was shown that mice treated with DHEA developed PCOS-like ovaries. One small pilot study in which women were pre-treated 2 months prior to IVF with DHEA improved their responses. One of the larger studies looked at 25 women with a history of poor responses and reported that treatment with 75 mg/day for 4 months improved several IVF parameters. Another study published in 2010 studied 26 women with a history of poor responses and randomly assigned them to take DHEA or not with their IVF treatment and reported improved estrogen levels and embryo quality. Although this was reported as a “randomized, prospective” study, there were serious methodology problems with the study so we still have to say that the “gold standard” randomized, prospective, double-blind clinical trial with enough patients to accurately address the issue of DHEA for poor responders has yet to be reported. Nevertheless, there is no evidence at this point that DHEA is harmful or has any significant side effects. It is available over-the-counter at most nutritional supplement stores.
Because of the interest in androgens and follicular response, studies were undertaken using transdermal testosterone skin patches prior to ovarian stimulation. Initial published studies were very encouraging with regards to increasing the numbers of eggs recovered at IVF after relatively short treatments. Unfortunately, other studies have been unable to replicate the initial findings so the jury on testosterone is still out. It is possible that it is difficult, with transdermal skin patches or testosterone gel to get enough testosterone into the interior of the ovary, especially as compared to high doses of injectable testosterone used to cause virilization in transsexual female-to-male patients.
CoQ10 is a vitamin-like anti-oxidant molecule found in the mitochondria of cells. These are the energy-producing organelles inside all cells. It has been found that concentrations of CoQ10 decline in egg cells after age 30. Studies in mice have shown that supplementing older mice with CoQ10 leads to decreased mis-alignment of chromosomes and decreased DNA defects as well as an increase in litter sizes. Studies in women have been extremely limited. One group investigated levels in the fluid in follicles surrounding egg cells and found that the levels were higher when the eggs were mature and normal-appearing and lower when the eggs were more immature and appeared abnormal. Another very recent study in 27 patients undergoing IVF with chromosome testing of their embryos reported that women receiving 600 mg/day had 40.7% of their embryos testing abnormal compared to 54.8% in women receiving placebo. Again, more studies need to be done to confirm the benefits but there does not appear to be any harm in supplementing poorly-responding women.
Human Growth Hormone is a pituitary hormone responsible for growth in childhood but also may play a role in maintenance of various tissues in adults. This is a relatively expensive injectable pharmaceutical medication that is highly regulated by the FDA due to abuse by some athletes. Several published studies have suggested that it may be beneficial to add this hormone to stimulation regimens for IVF patients, especially patients over 40. Most of the investigators in this area have come to the conclusion that hGH increases the quality of eggs but not necessarily the quantity.
In summary, these are some of the currently-used supplements that may (or may not!) increase the numbers of eggs, quality of eggs and embryos and the overall success in achieving a healthy pregnancy in low-responding IVF patients. If you have further questions, please ask your PFC physician for more information about whether any or all of them might be right for you.
- Androgens and poor responders: are we ready to take the plunge into clinical therapy? Fanchin, R., Frydman, N., Even, M., Berwanger da Silva, A., Grynberg, M.,Ayoubi, J. Fertility and Sterility 96(5):1062-5., November 2011.
- Coenzyme Q10 content in follicular fluid and its relationship with oocyte fertilization and embryo grading. Turi A, Giannubilo SR, Brugè F, Principi F, Battistoni S, Santoni F, Tranquilli AL, Littarru G, Tiano L. Arch Gynecol Obstet. 2012 Apr; 285(4):1173-6. doi: 10.1007/s00404-011-2169-2.
- The value of growth hormone supplements in ART for poor ovarian responders. De Ziegler, D., Streuli, I., Meldrum, D., Chapron, C. Fertility and Sterility, 1069-76., November 2011.
- Addition of dehyroepiandrosterone (DHEA) for poor-responder patients before and during IVF treatment improves pregnancy rate: A randomized prospective study. Wiser, A., Gonen, O., Ghetler, Y., Shavit, T., Berkovitz, A., Shulman, A. Human Reproduction 25(10), 2496-2500. August 2010.
— Carolyn Givens, M.D.