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From the Townsend Letter
April 2013

Integrative Approaches to Infertility for Women
by Jaclyn Chasse, ND 
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Improving Female Fertility
Before we discuss the interventions researched to enhance fertility in women, it is interesting to note that far more research exists on interventions for men. This is likely due to the comparative ease of a study in men, where semen can be analyzed before and after an intervention to determine any effect on sperm parameters. For women, analysis is far more challenging, since egg retrieval is a far more invasive process. While the quantity of direct research on female fertility is relatively scant, there are some clinical gems worthy of noting. The remainder of this article will focus on interventions for women, as that is the topic of interest for this issue.

The process of conception is very complex, and while a man's contribution is significant, the mother's role has more breadth, and therefore there are more areas that could be dysfunctional in a woman trying to conceive. It's essential to identify where a fertility problem lies, and a proper work-up followed by an accurate diagnosis is the first step to effective treatment of infertility. It is necessary to confirm that a woman is ovulating, and that intercourse is timed appropriately around ovulation. As a woman tries to have children later in life, it also has become increasingly important to confirm that her eggs are good enough quality to conceive and to develop into a healthy child. Lastly, a woman's uterine environment must be appropriate to allow for implantation. Inadequate uterine lining thickness, excess inflammation, and many other causes can contribute to an inability of the embryo to implant properly and create the tether to sustain its life.

One of the most common causes of anovulation or irregular menses is polycystic ovarian syndrome (PCOS). PCOS affects 10% of women of reproductive age and is characterized by anovulation or infrequent menses, cysts on the ovaries, blood sugar dysregulation, and hormone imbalances such as increased testosterone or an increased LH/FSH ratio. Women with PCOS may experience difficulty maintaining a healthful weight, hirsutism, and frequently, infertility. The current standard of care for women with PCOS is insulin sensitizing agents such as metformin, but metformin is not effective in inducing ovulation in many patients.34

Because the phosphoglycan that mediates insulin action contains D-chiro-inositol, and because this phosphoglycan is deficient in women with PCOS, it was postulated that restoration of adequate inositol levels may play an important role in restoring proper hormonal function in women with PCOS.35 Studies have demonstrated the significantly superior effect of inositol in sensitizing cells to insulin, compared with metformin, in PCOS patients as well as restoring ovulation, which is particularly important for women with PCOS trying to conceive.36 Administration of both D-chiro- and/or myo-inositol, typically at a dose of 4 grams daily, has been shown to improve insulin sensitivity, improve ovulatory function, decrease serum androgens, decrease elevated blood pressure, decrease elevated plasma triglycerides, and improve oocyte quality in women with PCOS.37,38 Myo-inositol is the preferred form to dose, as it seems to perform better than the more expensive D-chiro-inositol.39

In women with PCOS who are undergoing Clomid-supported cycles, coadministration of N-acetylcysteine at a dose of 1200 mg daily from cycle day 3 through 8 significantly improved ovulation rates from 17.9% in the control group to 52.1% in the treatment group. In addition to an increased ovulation rate, women in the treatment group also produced more mature follicles, had greater endometrial thickness, higher follicular estradiol levels, and increased luteal phase progesterone levels.40 These are all signs of improved hormone balance and enhanced fertility.

A thin uterine lining can prevent proper embryo implantation. Unfortunately, a thin uterine lining is a common side effect of "fertility-promoting" medications such as Clomid, or clomiphene citrate. Clomiphene citrate acts as an estrogen blocker to decrease the negative feedback signals that estrogen provides to the hypothalamus and pituitary glands. This communication block can result in enhanced production of GnRH and FSH, which provides additional stimulation to the ovaries to enhance follicular production. One downside of this medication is that with the blocking of estrogen comes the side effects of a decrease in endometrial development and cervical mucus production, both of which are enhanced by estrogen. For some women, clomiphene use may simply move their fertility problem from one of ovulation difficulty to implantation difficulty. Two small studies demonstrate the promise that black cohosh may have in protecting women who choose to take clomiphene citrate against these negative effects. In a 2009 study by Shahin et al., 134 women were randomized to receive black cohosh extract 120 mg daily or ethinyl estradiol from cycle day 1 through 12. The women receiving black cohosh extract needed fewer days for follicular maturation, had a thicker endometrium, and had higher estrogen levels (p  < 0.001). Also, their luteal-phase progesterone levels were higher, which can indicate an improved quality of the corpus luteum that develops in the follicular phase of a women's menstrual cycle. Clinical pregnancy rates were also significantly higher in the black cohosh group versus the ethinyl estradiol group (36.7% versus 13.6%).41,42 Black cohosh appears to provide a safe and viable option for women who experience negative side effects of clomiphene citrate stimulation.

Improving Ovarian Reserve
For women over 35, ovarian reserve can be one of the most challenging areas of fertility to overcome. Ovarian reserve describes the quantity and quality of eggs produced in response to natural or drug-stimulated follicular development. It is unknown whether poor ovarian reserve is caused by an abnormally rapid loss of a normal-sized follicular pool, or by a normal rate of degradation of an abnormally small follicular pool. Either way, conventional medical options are limited, and women diagnosed with a low ovarian reserve are typically recommended egg donation as their only option.

Just as oxidative stress plays a significant decrease in quality of sperm in men, it is also believed to play a major role in the reduction of egg quality in women. For women with decreased egg quality, additional antioxidant support should be considered over and above that provided through a standard prenatal vitamin.

An Italian study published in 2010 has suggested that melatonin may be a useful antioxidant to support egg quality. 65 women undergoing IVF were randomized to receive myo-inositol and folate or an identical preparation of the same combination plus melatonin. The melatonin group experienced a significant increase in the number of mature oocytes and decrease in the number of immature oocytes produced after GnRH stimulation. There was no difference in total oocytes produced, but the melatonin group had a significant increase in quality and maturity.43 A similar study showed positive trends in clinical pregnancy rates and implantation rates in the melatonin group, although the results were not statistically significant.44 In another study by Tamura et al., 115 women with a history of failed IVF and low fertilization rate of their oocytes (<50%) in previous cycles were randomized to receive melatonin 3 mg daily at bedtime or placebo. Fertilization rate improved significantly in the melatonin group only after 8 weeks of supplementation.45,46

DHEA is commonly prescribed to women with poor ovarian reserve. In fact, it is used by over one-third of all IVF centers worldwide.47 DHEA is thought to improve ovarian function and ovarian reserve by promoting preantral follicle growth and reducing follicular atresia. Several studies have looked at the effect of DHEA supplementation in women undergoing IVF with decreased ovarian reserve, and generally, supplemented women have higher pregnancy rates and lower miscarriage rates (by reducing aneuploidy), especially among women over age 35.48 One such study supplemented women with 25 mg of DHEA three times daily. Supplementation significantly increased women's levels of anti-Müllerian hormone (AMH;  p = 0.002), a hormone produced by developing follicles that is currently considered the best indication of good egg quality and quantity. Improvement of AMH was approximately 60% (p < 0.0002), and longer use (up to 120 days) showed the greatest improvement. In addition to improvement in tests for egg quality, treated women also experienced a significant increase in the number of fertilized oocytes (p < 0.001), normal looking day 3 embryos (p = 0.001), transferred embryos (p = 0.005), and improved total embryo scores (p < 0.001).49,50 It is interesting to note that in the studies of DHEA supplementation, there are few reported side effects; however, supplementation of DHEA at 25 mg three times daily is a high dose in this author's opinion, and should be done only under the supervision of an experienced clinician.

Infertility has become a widespread problem in the US. Amazingly, the rate of infertility is the same as the rate of breast cancer in the US. Although the suffering incurred with infertility is not comparable to that of breast cancer, couples experiencing infertility do incur amazingly high stress levels, and increased rates of divorce, depression, and anxiety. Furthermore, those suffering with infertility often do so in isolation, as they feel a social stigma around not being able to easily conceive. While rates of fertility are on the rise, so are the rates of the use of technological medical approaches to overcome infertility. While procedures such as IUI and IVF are not without merit, there is little focus on correcting any underlying dysfunction, deficiency, and imbalance leading to trouble conceiving. Integrative practitioners serve an essential bridge to bring these health-promoting practices into the field of reproductive endocrinology, and should take a leadership role in bringing preconception practices to every couple wanting to have a child.


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