Traditional Chinese medicine treatment of the IVF patient

Kidney deficiency (and egg quality)

A large number of the women seeking help for infertility from the Chinese medicine clinic and the IVF clinic fall into a Kidney deficient category. These are often women in their late 30s and early 40s, or those who are depleted by overwork. If they have already attempted some IVF cycles they will often have heard from their specialist that their egg quality is not so good.

Egg quality is something mentioned in hallowed terms in IVF clinics because it is somewhat unfathomable and seemingly beyond the influence of the IVF specialists or scientists. Some ovaries age more quickly than others and unfortunately, neither acupuncture nor Chinese herbs (nor much else) can increase the number of eggs left in the ovary or change the integrity of the chromosomes. Nobody, not even the most skilled doctor, can improve the genetic quality of an ‘old’ egg because its genetic material was created decades earlier, when the woman was an embryo herself, and it has been subject to the relentless cellular wear and tear of decades. However, there is more to an egg than just its DNA and it is in consideration of its other components that we hope to apply some influence.

The environment that eggs occupy during their lengthy maturation process inside the follicles of the ovary has an impact on what shape they are in before meeting a sperm (with or without an IVF embryologist in attendance). They need a good blood supply, sufficient oxygen, adequate amounts of the right nutrients, the right hormone signals and the capacity to supply enough energy to the embryo.

This has important implications, particularly for eggs that are coming from slightly older ovaries (or where AMH levels are low or FSH levels are elevated) and possibly for eggs coming from women with PCOS or endometriosis.

The question is, can Chinese medicine be used to rejuvenate some oocyte characteristics by improving delivery of oxygen and nutrition to the developing egg and enhancing capacity to make energy (ATP), thus increasing the chances of making viable embryos? There is evidence to say that it can.

Research has shown that eggs that come from follicles with optimal blood supply and oxygen content have higher fertilization rates and developmental potential leading to improved IVF outcomes.¹

The blood supply to the follicles in older ovaries is reduced at the later stages of their development, meaning that these eggs do not receive optimal oxygen or nutrition,² which may be a contributing factor to the poor quality of older eggs. Unlike chromosomal integrity, this is something we can influence.

Acupuncture has been shown to promote the growth of new blood vessels (angiogenesis)³ and to specifically increase blood flow to the ovaries.⁴

In summary, we could say that the use of certain acupuncture point combinations, stimulated with a gentle electrical pulse can promote blood supply, and delivery of nutrition and oxygen to the follicles and therefore hope to improve their potential to fertilize and create embryos. Another way we may be able to improve egg quality is by improving the egg’s capacity to make energy so that it can impart this enhanced capacity onto an embryo after fertilization. The organelles in the cytoplasm of the oocyte, called the mitochondria, have been identified as possible markers for egg and embryo quality. These powerhouses of the cell, which are donated from the egg to the embryo, are responsible for providing energy for cell division and metabolism in a process called aerobic respiration.

Those oocytes that consume more oxygen before fertilization (i.e., have more active aerobic respiration), are the ones which form better quality embryos.⁵

The early pre-implantation embryo occupies a low oxygen environment (the fallopian tube or the Petri dish in the IVF lab) and relies on anaerobic as well as aerobic respiration. By the time the embryo reaches the uterus (Day 5 or 6), it needs not only good numbers of mitochondria but optimal mitochondrial function and ATP production via aerobic respiration to succeed in implanting.⁶

It is at this level that Chinese medicine hopes to exert some beneficial influence by ensuring the number and activity of the mitochondria in the ripening eggs is optimal. We know that eggs with more energy (ATP) have a better chance of making viable embryos and that the rate of division and successful implantation of embryos has more to do with how much energy they have than with maternal age. However, the mitochondria of older eggs are not so good at producing ATP⁷ and the eggs of poor responders to IVF drugs have three times less mitochondria than those of good responders.⁸

Similarly, it is known that older follicles have fewer antioxidant defenses against cellular damage caused by aerobic respiration and oxidative stress,⁹ and that this too is related to poorer IVF outcomes.¹⁰

The ART embryologists have been experimenting with adding younger mitochondria to the eggs from older women to see if this helps to make better embryos. The Chinese herbalist uses Kidney Yang herbs to do the something similar. These are the herbs that we saw added to fertility formulas in the late stages of the follicular phase (Phase 3) (see Ch. 4).

Interestingly, researchers have shown that it is precisely these particular herbs (used in fertility clinics in China for many centuries!) that markedly enhance mitochondrial activity and ATP production in laboratory studies on mice, while other herb categories such as Qi or Yin tonics have little effect on mitochondrial ATP production. These same herbs were shown to enhance antioxidant defenses at the cellular level.¹¹

What the ancients knew from trial and error scientists are now proving in labs. We must bear in mind however, that for the doctor of TCM, the clinical experience of thousands of years of Chinese herbalists treating infertility carries more weight than the lab findings examining mouse tissues. That is not to say it isn’t satisfying when a new science can verify an old one.

Thus, we might surmise that the Kidney Yang herbs that are taken in the days leading up to ovulation, when the egg is maturing, can boost mitochondrial function, which then gives a newly formed embryo an advantage by dint of increased energy making capacity to aid development and successful implantation.

The herbs in Box 11.1 were found to increase ATP output in mice tissues. They are listed in descending order of effectiveness.

Thus, when we are choosing which Yang herbs to add to our formulas in the days before ovulation, we might consider not only the characteristics we examined in Chapter 4 when constructing our formulas but also the potency they have shown in laboratory tests.

Back to the clinic and to our patient who is concerned with egg quality, we must recognize that we have a condition, Kidney deficiency, that is not one that responds quickly to treatment – it takes time, rest, regular routines, reduced stress, adequate sleep, good nutrition and the sorts of treatments a doctor of Chinese medicine can provide.

However, time is usually the one thing these women often don’t have. They are anxious to get to the IVF clinic, or back to the IVF clinic, hounded by the ticking of the biological clock and the sound of their IVF specialists voice saying, ‘You shouldn’t have left it so long!’ But the sad irony is that for these women, IVF or repeated IVF, only drains the Kidney further.

Heart and Liver Qi stagnation (and sleep and stress)

As mentioned above, it is women with Heart and Liver Qi stagnation who benefit greatly from treatment during the IVF cycle, however preparatory treatment to regulate the cycle and calm the nervous system will also pay dividends. Sometimes in a big way, these patients are quite likely to respond quickly to acupuncture and may conceive before the (next) IVF cycle.

Treatment protocols following the 4 Phases are those found in Chapter 4. If, however, a simpler approach is required, then combining an expanded version of Gui Shao Di Huang Tang with elements of Xiao Yao San or Gan Mai Da Zao Tang could be taken all month to prepare your patient and her ovaries for IVF.

Blood stagnation

Treatment in the 3 cycles before IVF can be very useful in going some way to resolving blood stagnation, which might affect oocyte or endometrium quality. Most Blood stagnation pathologies affect the endometrium, whether they be ones that require surgery such as large submucosal fibroids or polyps, or ones not always so amenable to surgery such as adenomyosis, endometritis or diffuse endometriosis. Some forms of Blood stagnation appear to affect the egg quality as well as the endometrium quality, and this is also amenable to treatment. For example there is some evidence to show that Chinese herbs improve egg quality in patients with endometriosis by reducing inflammatory markers in the follicular fluid.²²

Treatment protocols are those described in Chapter 4 with a large emphasis on clearing stagnation during Phase 1, during the menstrual flow. In this way, we hope to alter the endometrium and the way it forms in the hope that this will reduce risk of implantation failure. This sort of treatment aims to minimize the effect of immune and clotting factors which can jeopardize implantation and placenta formation.

Improving the hormonal and immune milieu of the ovaries of these patients with endometriosis with acupuncture or Chinese herbs in the months before doing IVF could have benefits similar to treatment of older ovaries, i.e., an improvement in the egg quality.

The progress of your treatment may be effectively monitored by menstrual symptoms such as pain or the nature of the menstrual flow.

A simplified approach using herbs in preparation for IVF would be the use of a Phase 1 type of formula such as that below, during the period, and at other times of the cycle if natural conception is not being attempted. Where your patient is still attempting to conceive, use the formula below (Tao Hong Si Wu tang modified) during the period followed by the next formula (Gui Shao Di Huang tang plus Tao Hong Si Wu tang modified) for the rest of the cycle to prepare the ovaries for the IVF drugs.

Phlegm-Damp (and weight loss)

Blockages caused by Phlegm-Damp should be addressed before IVF. Although mucus secretions in the fallopian tubes will be circumnavigated by the IVF process, the presence of Phlegm-Damp in the Uterus does not create a desirable environment for the transferred embryo.

Preparation for IVF for men

It is worthwhile treating male factor infertility even if the couple plan to do IVF with ICSI. If the sperm vitality improves, ICSI may not be necessary. If it improves enough, IVF may not be necessary! (For the treatment of male factor infertility, see Ch. 7.)

4-Phase TCM treatment during the IVF cycle

Treatments according to the 4 Phases we described in Chapter 4 can be modified for use during the IVF cycle. In Chapter 4, when we applied the 4-Phase treatments we maintained a close awareness of the natural physiology of the menstrual cycle and applied treatments that followed these. However, in the case of the IVF patient, we must now be aware of the physiology of the drug manipulated ovary. Rather than enhancing the natural processes of the menstrual cycle as we did in Chapter 4, we must now track and support what are essentially pathologic states as some of the pituitary and hypothalamus activity is shut down and the ovaries are artificially hyper-stimulated.

Suggestions made here for herbal prescriptions to be taken during the IVF cycle (for those patients who have a history of poor response to IVF drugs, as discussed above) follow the requirements of each of the 4 Phases of the menstrual cycle, manipulated as it is. However, in comparison with the complex and many layered approach to treatment of infertility the doctor of TCM takes as primary practitioner, here we take a simpler role as a support practitioner to the IVF specialist.

We need to be clear about what it is exactly that we are supporting in this physiologically artificial and manipulated situation. Essentially, we are assisting the patient emotionally and her ovaries physiologically. Our aims are to:

Assisting the ovaries as they are induced by non-physiologic doses of FSH to ripen multiple eggs means in TCM terms supporting the Kidneys; this is usually achieved with the use of herbal medicine. This sort of treatment will most often be requested by the ‘poor responder’, as we discussed above. The ovaries of women with depleted Kidney Qi, or those who have done a lot of IVF cycles, tend to respond poorly to stimulation by IVF drugs.

IVF patients who do not need this support (the ‘good responders’ who produce adequate numbers of eggs and younger women) may request Chinese medicine treatment during their IVF cycle to deal with stress, anxiety and side-effects. This is best achieved with acupuncture and administration of herbal medicine is not indicated in these cases.

The guiding prescriptions offered as support for IVF patients who are not good responders and have a history of failed IVF cycles address the immediate situation (namely, ripening of ovarian follicles) as much as the patient with her original infertility diagnosis. Hence, compared with the guiding formulas described in Chapter 4, there are fewer modifications required relating to the original cause of fertility.

Here, we will describe the 4 Phases of the menstrual cycle modified to take into account the effects of the drugs used in an IVF cycle. For women on a long downregulated IVF cycle, drugs will be administered before we actually get to Phase 1 (the menstrual phase) and these GnRH agonist drugs tend to delay the period. At this point, what is required is regulation of Qi and Blood to encourage menstrual flow and to prevent stagnation. Acupuncture to regulate the movement of Qi and Blood is particularly helpful at this time. Additionally, we want to support the Kidneys and their Jing, as they prepare for the demands on them once the stimulating drugs commence. Except in the circumstances described above, herbs are not usually prescribed during this downregulating phase and if your patient has been taking herbs in the preparation phase for IVF, then she will usually be advised to discontinue them before she starts the GnRH agonist.

Once the period arrives, we shall arrange our treatment according to the 4 Phases as described below.

Effects on implantation and pregnancy rate

It is thought that the acupuncture points applied on the day of embryo transfer may confer some advantage to the process of implantation.

The original investigators said that they chose acupuncture points that ‘relax the uterus according to the principles of TCM’ and that ‘because acupuncture influences the autonomic nervous system, such treatment should optimize endometrial receptivity.’ They state that the points they chose ‘stimulate Taiying meridians (Spleen) and Yangming meridians (Stomach, Colon) to result in better blood perfusion and more energy in the uterus’ and that stimulation of other points, aimed to ‘sedate the patient and stabilize the endocrine system.’

A number of subsequent reviews have postulated that the effect of acupuncture given at the time of transfer might be to reduce contractions in the uterus, change the immune milieu, increase blood flow or to relax the patient and reduce cortisol. It has been noted that pregnancy and implantation rates are negatively impacted by uterine contractions at the time of transfer.³⁵ One study on rats found that acupuncture reduced uterine contractions.³⁶

One group thought that acupuncture might reduce endometrial motility and uterine contractions and therefore facilitate implantation of the embryo but when they tested this theory with ultrasound, they found little difference in the movement of the uterus at transfer between acupuncture and non-acupuncture groups.³⁷

Another clinic³³ has shown that acupuncture (whether by pricking the points or penetrating the points) reduces levels of the stress hormone cortisol, and also reduces the vascularity of the endometrium. They wondered if just having the patients lie down and relax before their embryo transfer might have the same result but found that it didn’t and that the acupuncture was the active intervention.

We don’t yet know exactly what effect cortisol level has on implantation, although stress has definitely been shown to be associated with lower fertility³⁸ and lower implantation rates.²⁶

Another study looked at the effect of repeated electroacupuncture treatments (using points which have been shown to increase blood flow to the uterus) before and during the drug phase of an IVF phase, on the serum cortisol and prolactin levels. They found that cortisol and prolactin levels were higher (cortisol still in normal physiologic range, but prolactin higher than normal physiologic range) in the acupuncture group than the control group for the week prior to embryo transfer, although the difference was not sustained after EPU.³⁹

Endorphin levels, or other stress markers like adrenalin, sympathetic nervous system activity or heart rate have not to-date been measured in trials looking at the effect of acupuncture on implantation.

Acupuncture points used on the day of embryo transfer (ET)

Nearly all researchers using acupuncture (or electrical stimulation on acupuncture points) at the time of ET have used (for the treatment group) the original points used in the trial in 2002.⁴⁰ Results have varied (in terms of pregnancy rates), despite use of the same points. The acupuncture protocol was varied in some trials.^41–43 Box 11.3 summarizes the points used in these trials.

Another small study looked at the effect of hypnosis and another at the effect of laughter on IVF patients having embryo transfer. In both cases, the ‘treatment’ groups showed a higher pregnancy rate than the control group, indicating that stress reduction might have a beneficial effect on implantation.^44,45

Effects on endometrium

We do not yet fully understand the effects of increased or decreased blood flow to the uterus or its lining on implantation. Electroacupuncture performed on certain points appeared to increase blood flow to the uterus of women taking downregulating drugs of the type used in IVF cycles in a small clinical trial, although these women were not actively doing IVF⁴⁶ and the endometrium itself was not examined in this study.

One group,³³ found that acupuncture (using the Paulus pre-transfer points, manual stimulation only) performed just before embryo transfer during an IVF cycle, reduced vascularity or endometrium volume. Less vascularity of the endometrium may promote a more hypoxic environment and since the mammalian embryo develops in a low-oxygen environment (especially during its first 5 days when it is normally traveling down the fallopian tube to the uterus), this may confer an advantage. This local hypoxia promotes angiogenesis (growth of new blood vessels) in anticipation of the demands of the growing embryo for oxygen and nutrients.^47,48

Interestingly, acupuncture has also been shown to promote angiogenesis (in rat brains, using EA on DU-26).⁴⁹

It may be an interesting combination of acupuncture-induced reduction of endometrial vascularity and hypoxia, combined with an increased stimulus to angiogenesis from both the acupuncture and the hypoxia that benefits implantation. If some types of acupuncture treatment do indeed promote a hypoxic environment that is advantageous to implantation and early embryo development, TCM doctors would be advised to avoid applying those acupuncture treatments which have been shown to increase blood flow to the uterus (see Box 11.4, below) at the time of embryo transfer, or the days following. In fact, these points were included in those treatments applied during the drug stimulation phase of the IVF cycle when the uterine lining is thickening. Most acupuncturists would be reluctant to apply electroacupuncture to the lower back, abdomen or Spleen points at the time of implantation in any case.

Additionally, we should be wary at this time of using herbs that have been shown to increase blood flow to the uterus.⁵⁰

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49. Du, Y., Shi, L., Li, J., et al. Angiogenesis and improved cerebral blood flow in the ischemic boundary area were detected after electroacupuncture treatment to rats with ischemic stroke. Neurol Res. 2011;33(1):101–107.

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