Nutritional Supplements to Improve Fertility?

Most fertility supplements lack scientific evidence of efficacy. CHR recommends just a few, depending on each patient’s needs.

So, you are trying to conceive, and your girlfriend told you about all those supplements you immediately should start taking; a long list of at least 10 different ones. Just thinking about swallowing all of these pills every day makes you dizzy. And what about the costs? Insurance rarely pays for supplements and you rightly ask, will they really make a difference?

The honest answer is that, with very few exceptions, they, likely make NO difference!


NOTICE OF POTENTIAL CONFLICT
We want to point the attention of our readers to a potential economic conflict: CHR and some of its physicians are owners of a number of US patents, which claim fertility benefits in women with supplementation of androgens (male hormones), especially a hormone called dehydroepiandrosterone (DHEA). In the US, DHEA, paradoxically, is considered a food supplement, while elsewhere in the world, like other hormones, it is considered a drug. Since CHR and some of its physicians receive royalties from companies that sell DHEA as a fertility nutraceutical, CHR, in full disclosure, wishes to point out this fact as a potential conflict of interest, readers of this article should consider.


There is very little evidence that in almost any medical specialty nutritional supplements make much of a difference. Studies in various medical fields have shown this over and over again; yet, the industry is growing, and people buy ever increasing numbers of supplements. If anything, in pregnancy and/or in preparation for pregnancy, there is a general feeling that supplementation may be especially useful.

To a degree that is correct. For example, there is considerable evidence in the literature that suggests that supplementing folic acid during pregnancy lowers the prevalence of spinal fusion defects in offspring. Whether full prenatal vitamins make any difference is, however, already much more controversial, unless, of course, specific deficiencies are discovered through objective laboratory testing. So, for example, if a patient has low Vitamin D levels, it, of course, should be corrected with a supplement, or if a patient is diagnosed with anemia, supplementation with iron may be appropriate.

When it comes to infertility, the considerations are similar. If a vitamin deficiency is diagnosed during a basic fertility evaluation, it makes sense to supplement; if no such deficiencies are diagnosed, automatic supplementation really has to be questioned.

Vitamin D

A good example is Vitamin D deficiency. A number of studies recently claimed that abnormally low levels could negatively affect IVF outcomes. A study CHR investigators performed was, however, unable to confirm any adverse effects of low levels of Vitamin D on IVF outcomes. CHR’s physicians, still, supplement abnormally low levels but are much less concerned about them than they used to be before completing their study, which soon should be published.

Other Vitamins

Many women in fertility treatments supplement with a whole array of other vitamins as well, including Vitamin C, Vitamin E, Vitamin B-Complex or individual Vitamin B components, etc. There is little, if any, evidence that any of these supplements affect fertility treatments in any significant ways, unless they have been established to be deficient.

Non-Vitamin supplements for female fertility

There are also increasing numbers of non-Vitamin supplements being marketed to female infertility patients, either as individual products or in combination products containing multiple ingredients. Single substance promotions one finds all over the web include zinc, magnesium, selenium, beta-carotene, royal jelly, L-arginine, L-carnitine, fish oil and omega 3 fatty acids, acai, nicotinamide riboside, NAC (N-acetyl-cysteine) and melatonin. Among all of these, we are aware of really only one Japanese study, involving melatonin, which claimed benefit in improving ovarian function in women with low functional ovarian reserve. How all of the other products have become so popular, is really quite amazing because none of them has been demonstrated to cause any positive effects on either female or male fertility.

Herbs

Likely due to the increasing popularity of Eastern (Chinese) medicine, we have in recent years also witnessed a considerable increase in use of herbs. Agnus Castus (Vitex Agnus Castus) is advertised as “restoring hormone imbalances” and “increasing fertility” but we are unaware of studies to prove this point. Moreover, since Chinese herbs often contain hormones, they can interfere with hormone assay results. They, indeed, can also interfere with the function of various medications, such as birth control pills. At least one study in the medical literature, published by European colleague’s, claimed lower IVF pregnancy rates in cycles where patients were exposed to herbs. For all of these reasons CHR, therefore, strongly recommends that patients avoid herbs while in IVF cycles.

What CHR recommends

In contrast to many other fertility centers, CHR does not have a “supplement list” that is prescribed to every patient. Indeed, CHR does not believe in the concept of treating everybody in the same way. Very much to the contrary, one of the cornerstones of CHR’s treatment philosophy is individualization of care, and that also applies to supplements.

Dehydroepiandrosterone (DHEA)

As already noted above, CHR is quite skeptical about use of supplements in fertility treatment since for the vast majority of supplements offered in the market place, there is really no supportive evidence of efficacy in improving fertility. CHR, therefore, concentrates on only a few: The supplement CHR prescribes the most is dehydroepiandrosterone (DHEA). Anywhere but in the U.S., DHEA is really not considered a food supplement but a drug. Indeed, because it is often abused by athletes and body builders, DHEA is a controlled substance in many countries. The reason why in the U.S. it is available without prescription is a long story, involving the usual political interests that so often are responsible for rather strange policy decisions. DHEA, therefore, is available in the U.S. from a large number of resources as an over-the-counter product, and often of quite mixed quality.

Though DHEA is available without prescription, CHR, nevertheless, considers it a pharmacological product that should be produced under strict quality control and prescribed by a physician. CHR readers may be aware that CHR investigators hold a good number of U.S. patents (see Conflict Statement above) , claiming fertility benefits from supplementation with DHEA (and other androgen hormones) in female infertility. For that reason, any company that wants to sell a DHEA product for female fertility purposes in the U.S., must be licensed by CHR. This gives CHR the opportunity to exert a certain degree of quality control over products that make fertility-related claims. Currently, only two products have been licensed by CHR: Fertinatal™, produced by Fertility Nutraceuticals, LLC, in NYC, and a DHEA product offered by Theralogix, LLC, in Rockville, MD. CHR prefers the former because it represents the exact composition and particle size of the DHEA CHR investigators used in their initial groundbreaking clinical research projects, reported in the medical literature. Those studies laid the groundwork for the worldwide utilization of DHEA (and other androgens) we now witness in the treatment of hypo-androgenic female infertility.

CHR investigators a good number of years ago reported in collaboration with colleagues from Toronto, Canada, that DHEA supplementation not only enhanced pregnancy chances but also reduced miscarriage rates, and that this reduction, likely, was caused by decreases in embryo aneuploidies. Most remarkably, these effects became only visible after age 35, and increased with advancing female age. CHR, therefore, recommended to combine standard prenatal multivitamins with a low dosage (25mg daily) of DHEA for women above age 35 who were attempting to conceive on their own. Fertility Nutraceuticals, LLC, indeed, started producing such a product, and CHR still recommends it for women above age 35 with no fertility problems who are trying to conceive spontaneously. The dosage of 25mg is only one-third of the therapeutic dosage recommended to women who are infertile and hypo-androgenic.

Coenzyme Q10 (CoQ10)

CHR also quite extensively prescribes Coenzyme Q10 (CoQ10), though one must acknowledge that there is not a single CoQ10 study in the literature that has shown fertility benefits in women. Studies in small female animals have demonstrated benefits but humans are not mice, and it is always dangerous to uncritically extrapolate animal data to humans. What convinced us at CHR that there may be value in CoQ10 supplementation was that our urology colleagues have been able to demonstrate benefits on semen quality from CoQ10 supplementation. Considering absence of side effects, relatively low costs, supportive animal data and the fact that male gametes appear to benefit from CoQ10 supplementation, CHR’s physicians came to the decision to consider CoQ10 a co-supplement to DHEA in all women with low functional ovarian reserve to improve egg quality. At the same time, we would welcome supportive studies in humans to confirm our decision. In males, CoQ10 is the only supplement CHR recommends.

Anti-Inflammatory Mix

As CHR recently addressed in the VOICE, it is becoming increasingly obvious that inflammation plays a much bigger role in female infertility than has been appreciated. CHR investigators associated elevated C-reactive protein (CRP) with significantly lower IVF pregnancy rates and elevated interleukin-6 (IL-6) levels with significantly increased miscarriage rates. Consequently, CHR treats evidence of inflammation with anti-inflammatory prescription medications much more aggressively than in the past. Concomitantly, we are, however, also exploring the use of a new supplement that recently entered the market under the name Conflam Forte, produced by above noted Fertility Nutraceuticals, LLC in NYC, and made up of a number naturally occurring anti-inflammatory ingredients.

In summary, non-prescription food supplements in our opinion have only a rather finite role to play in modern fertility care. That DHEA is the only such supplement we can wholeheartedly recommend, speaks for itself, since DHEA is a natural hormone men and women produce in their bodies. It, therefore, is a drug and not a food product under any definition. Though now routinely prescribed all over the world, and in its efficacy supported by considerable animal as well as human experimental evidence, even DHEA supplementation has remained, however, somewhat controversial, and there are good as well as bad reasons for that: In medicine it is always better to be skeptical than to jump into unsupported therapies, and it is true that nobody has yet published a properly powered prospectively randomized study of DHEA. CHR has attempted twice but had to abandon both attempts because women did not want to be randomized (i.e., have a 50% chance of receiving a placebo over many months). Studies in various animal models, however, established an excellent biological framework in explaining the clinical effectiveness of androgen supplementation in hypo-androgenic infertile women, and clinical studies in humans with lower levels of evidence also strongly support androgen supplementation in such women.

Not everybody agrees, however, with what research has quite convincingly demonstrated: One colleague with a prominent website, for instance, appears quite unfamiliar with the conversion biology of DHEA to testosterone when making some rather strange statements in warning against DHEA supplementation in infertile women. He, for example, claims that “by causing testosterone overload, such therapy could be highly detrimental to some women at risk for hyperthecosis.”

What makes this warning even stranger is that he specifically refers to older women and women with PCOS as threatened by DHEA supplementation. No sane fertility specialist would, of course, ever treat an already hyper-androgenic PCOS patients with DHEA but we are not sure that this colleague has already read up on the so-called hypo-androgenic PCOS-like phenotype, repeatedly discussed in the VOICE, which greatly benefits from DHEA supplementation. And practically every woman above age 40 is hypo- and not hyper-androgenic, which means that her ovaries would benefit from higher testosterone levels. Finally, we are really wondering about the concept of hyperthecosis, and how one diagnoses this condition in clinical practice in the first place?

So, let us, therefore, explain a few important issues regarding DHEA (or androgen) supplementation in general:

  • The recommended dosage of DHEA (25mg TID, p.o.) is roughly equal to the daily DHEA production rate of a young female adult person, therefore quite low and practically never will raise testosterone levels into toxic range;
  • The principal advantage of DHEA over direct testosterone administration lies in the fact that different organs (the ovaries included) maintain varying “normal” testosterone levels by picking up only as much DHEA out of circulation as they need to reach those desired levels. DHEA and DHEAS, otherwise, circulate as storage capacity for future testosterone production, while by themselves being mostly inert as androgens because of their very low affinity to the androgen receptor;
  • Responsible DHEA (androgen) supplementation, of course, requires baseline level determinations (one treats only hypo-androgenic women) and follow-up testing to determine when testosterone levels have reached the desired range, and an IVF cycle can be initiated;
  • Reaching toxic testosterone levels is really not the problem; what sometimes does become apparent with appropriate monitoring of testosterone levels is that a small minority of patients (much more frequently observed in women of African descent than in other races) do not convert DHEA well to testosterone. The genetics of this were well described by Aya Shohat-Tal, PhD and her CHR co-investigators in 2015 in NATURE Reviews Endocrinology [11(7):429-441]. Those patients then require direct testosterone administration by gel or patch.

This is a part of the April 2018 CHR VOICE.

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.