Chapter 19 Endometriosis
OVERVIEW AND AETIOLOGY
Endometriosis is the abnormal growth of endometrial tissue in areas other than the wall of the uterus.1 The exact cause of endometriosis is unknown although a number of theories do exist. It is one of the more common causes of infertility in Western societies. However, sufferers may experience combinations of many underlying causes and no person is identical in their symptoms or causes. Theories in naturopathic medicine include the following (see Figure 19.1):
RISK FACTORS
Several risk factors need to be addressed in the patient with endometriosis. Although often hormonal or inflammatory in nature, removal of these risk factors may be enough to significantly reduce symptoms. Lack of exercise can increase levels of oestrogen and inflammatory mediators and reduce oestrogen excretion.9 However, strenuous physical activity during menstruation may increase risk. Epidemiological data also suggest that positive correlations of symptoms and occurrence are seen with increased cigarette smoking; increased carbohydrate, alcohol and coffee intake; stress; and low body mass index.10 Aromatase found in adipose tissue may also increase the formation of oestrogen.11 Therefore weight loss may be indicated in some patients.
CONVENTIONAL TREATMENT
Conventional medical treatment aims to reduce the symptoms of endometriosis and improve fertility. This can be done surgically (most often laparoscopic to remove tissue, although occasionally hysterectomy is required) or medically. Medical interventions focus predominantly on reduction of excessive oestrogen levels. These include those androgenic in nature, such as danazol or progesterone supplementation; inducing hypo-oestrogenic states by decreasing FSH and LH through the use of gonadotrophin-releasing hormone agonists (GnRH agonists); continuous hormonal contraception to stop bleeding; or aromatase inhibitors to block the formation of oestrogens, particularly in adipose tissue.1
KEY TREATMENT PROTOCOLS
Oestrogen modulation
Hypothalamic–pituitary–ovarian axis modulation
Oestrogen levels in the body may be affected by disruptions of the hypothalamic–pituitary–ovarian (HPO) axis. The anterior pituitary releases FSH (follicle stimulating hormone) and LH (luteinising
AROMATASE
Aromatase is an enzyme of the cytochrome P450 superfamily the function of which is to aromatise androgens, thereby producing oestrogens. Normally, it is found in the ovaries, and to a much lesser extent in the skin and fat. Aromatase is not present in the normal endometrium but is expressed aberrantly in endometriosis.2,12–14
Prostaglandin E2 (PGE2) was found to be the most potent known inducer of aromatase activity in endometrial cells.15,16 Inflammation may not only increase aromatase, but also make endometrial tissue more sensitive to its effects.17 Factors known to increase aromatase activity are hyperinsulinaemia, increased adiposity, obesity and ageing.18
Aromatase activity may be decreased by increased consumption of dietary phyto-oestrogens19 in addition to reduction in adiposity and inflammation.
hormone), which encourages oestrogen release from growing ovarian follicles. Ordinarily feedback loops regulate hormone release from the HPO axis, but in some reproductive disorders this may be disrupted. Herbal medicines such as Vitex agnus-castus20 and Cimicifuga racemosa21 may help restore proper functioning of the HPO axis through direct and indirect means. Exercise has been shown to both reduce oestrogen production and increase oestrogen excretion10 (see Chapter 18 on premenstrual syndrome and dysmenorrhoea).
Oestrogen-like compounds and oestrogen receptor activity
Many compounds—both natural and synthetic—may mimic endogenous sex hormones.4,22,23 Several chemicals in current industrial use may interfere with the body’s hormone responses. Compounds such as dioxins, polychlorinated biphenyls (PCBs) and bisphenols (found in pesticides, petrochemicals and plastics) may bind to and activate endogenous oestrogen receptor sites. However, unlike natural hormones these xenoestrogens (literally ‘foreign oestrogens’) may exert effects many times more potent than endogenous oestrogens.24 Phytoestrogens (literally ‘plant oestrogens’) also bind to and activate these oestrogen receptor sites although they are often much less powerful than regular oestrogen and therefore act as oestrogen modulators by preventing the more powerful compounds—endogenous hormones and the xenoestrogens—binding in excess oestrogen conditions but binding to empty sites in oestrogen-deficient conditions.25 A compound exhibiting this activity is known as a selective oestrogen receptor modulator (SORM)—similar in effect to the pharmaceutical compound tamoxifen. The isoflavones (such as genistein and dadzein) from soy products, lignans from lentils and flaxseed, coumestans from Trifolium pratense and flavonoids found in a variety of sources are examples of phytoestrogens. Sources of phytoestrogens are listed in the box below. Although most research has focused on phytoestrogenic compounds from soy products, most dietary consumption of these compounds in Western diets occurs from lignans.26 Different soy products may also vary in their phytoestrogenic content: soybeans, tofu and tempeh are good sources while soy milk is generally not. Studies suggest that Cimicifuga racemosa may contain negligible amounts of phytoestrogenic compounds while still exerting strong oestrogen modulating ability.13 This is thought to be related more to its effects on luteinising hormone. V. agnus-castus has also shown significant competitive binding to oestrogen receptors in vitro.27
Trifolium pratense | 1,767,000 |
Flaxseed (crushed) | 546,000 |
Soybeans | 103,920 |
Tofu | 27,150 |
Sesame seed | 8,008 |
Flax bread | 7,540 |
Multigrain bread | 4,798 |
Pumpkin | 3,870 |
Chickpeas | 3,600 |
Lentils | 3,370 |
Soy milk | 2,457 |
The generalisation that all phytoestrogens are inherently weaker than endogenous oestrogen is not correct. The herbs T. pratense and Humulus lupulus actually exert stronger activity in the body than endogenous oestrogen. This may make them therapeutically useful in oestrogen-deficient conditions—those associated with menopause, for example—but may potentially exacerbate symptoms of oestrogen-dependent disorders and render their use inappropriate in high doses in conditions such as endometriosis.28,29 It is also prudent to avoid herbs known to promote oestrogenic symptoms, such as Chamaelirium luteum and Dioscorea villosa. Studies suggest that long-term treatment with high-dose phytoestrogenic compounds (in excess of 150 mg of soy isoflavones daily for 5 years) can lead to endometrial hyperplasia.30 This suggests a role for lower doses associated with modified dietary intake for long-term management. Cruciferous indoles, in addition to their activity on oestrogen excretion and conversion, may also directly inhibit stimulation of oestrogen receptors by oestrogen or oestrogen-like compounds31,32 though the particular mechanism is unknown at this time.
Oestrogen excretion
Inadequate oestrogen excretion may result in excess circulating oestrogens. The main route of elimination of excess oestrogens is the liver. The major pathways of elimination are the phase II liver pathways glucoronidation, sulphation and methylation.35 These pathways bind the used hormones with a water-soluble substance, which can then be eliminated through bile and eventually faeces.
If toxins overload the system, these pathways can become congested. Cruciferous indoles, such as indole-3-carbinol (I3C) and di-indolyl-methane (DIM), found in brussels sprouts, broccoli, cabbage, garlic and other ‘sulfurous’ vegetables,36 are
particularly useful for the oestrogen-specific pathways as they induce enzyme reactions that assist with detoxification and conversion of 17β-estradiol to less active forms (2-hydroxyestrone as opposed to 16α-hydroxyestrone).37–43 While these trials are largely based on direct supplementation (of 300–400 mg/day of I3C or 100 mg/day of DIM) studies suggest food supplementation may also be effective.36,39,44 Herbs such as Silybum marianum and Bupleurum falcatum can also improve liver enzyme activity in regards to oestrogen clearance.45 Figure 19.2 shows examples of supplements, foods and herbs useful in improving liver function. Rosmarinus officinalis has been found to directly increase hepatic metabolism of oestrogens and reduce their uterotropic action in animal studies.46 Vitamin B complexes may increase the inactivation of oestrone in the body.47 Other useful treatment tools are listed in Table 19.2.
PHASE | INDUCE | INHIBIT |
---|---|---|
I∗ | Cruciferous vegetables51 | Legumes52 |
Garlic53 | Grapefruit juice54 | |
Smoking55 | Starfruit juice56 | |
Thymus vulgare57 | Taraxacum officinale58 | |
Adhatoda vasica59 | Mentha pieperita58 | |
Charcoaled meat products | Matricaria recutita58 | |
Niacin | Humulus lupulus60 | |
High protein diets | Glycyrrhiza glabra61,62 | |
Hypericum perforatum63 | Rosmarinus officinalis64 | |
Withania somnifera65 | ||
Echinacea spp.66 | ||
Chlorophyll36 | ||
Berberine-containing herbs67,68 | ||
Schisandra chinensis69 | ||
II∗ | Curcumin70,71 | Low protein status |
Vaccinum spp.72 | Zinc deficiency | |
Green tea73,74 | B12 deficiency | |
Cruciferous vegetables75–77 | Folic acid deficiency | |
Taraxacum officinale58 | ||
Humulus lupus60,78 | ||
Glycyrrhiza glabra61 | ||
Rosmarinus officinalis64,79 | ||
Thymus vulgare57 | ||
Adhatoda vasica59 | ||
Withania somnifera65 | ||
Flavonoids36 | ||
Schisandra chinensis80 |
∗ For simplification purposes, phases I and II have not been split into their components.
Phase I liver detoxification processes convert oestrogens to either 2-hydroxyoestrone (2OH oestrone), 16- or 4-hydroxyoestrone. 2OH oestrone is a ‘cancer-protective’ metabolite (oestrogen antagonist) and the latter two are ‘pro-carcinogenic’ (oestrogen agonists).48 Each of the enzymes involved are subject to genetic polymorphisms that are measurable in more complex cases. Other factors can also affect this oestrogen conversion (see Figure 19.3).48
The liver is not the only organ associated with oestrogen excretion. The entero-hepatic circulatory system will recycle sex hormones if intestinal transit time is sufficiently slow. If there is not enough fibre in the diet, the oestrogens will be recirculated before they are excreted. Increased fibre consumption has been associated with lower oestrogen metabolites.34 Fibre is also required to increase dioxin, PCB and other oestrogen-like molecules from the body in animal models.49,50
Supporting liver function
Healthy detoxification consists of both appropriate phase I and phase II detoxification. Phase I is a stage in which lipid soluble substances are transformed into intermediate substances via the cytochrome P450 set of enzymes.33 In many instances this may render substances even more toxic or otherwise reactive than previously.33 Therefore appropriate phase II detoxification processes need to be supported. Phase II processes make the intermediate substances from phase I detoxification water-soluble by conjugating them with amino acids like glucoronic acid, glutathione and glycine or undergoing processes such as methylation, sulphation, acetylation and sulphoxidation.33 These substances can then be excreted through the stool, sweat or urine (and to lesser extent lungs)—elimination pathways, which also need to be appropriately encouraged in detoxification.
Many studies are either in vitro or animal in vivo and therefore clinical significance often remains unknown. It should also be noted that there often exists a lack of in vivo–in vitro correlation with respect to studies on interaction of phase I interactions. For example, while Silybum marianum has documented in vitro evidence of induction of cytochrome p450 enzymes, in vivo evidence does not seem to suggest a significant effect.81–83 Further studies have also demonstrated that co-administration of S. marianum with other medications does not reduce levels of that medication, again suggesting no clinically significant interaction.84–87 The induction of CYP enzymes by H. perforatum also seems to bear little clinical significance when compared to in vitro results.88,89 However, quality issues need to be considered as evidence suggests that specific compounds in naturopathic medicines that vary from product to product may be responsible for this induction—for example, levels of hyperforin may be responsible for induction in H. perforatum products and these levels can differ significantly in different products.88,90 However, a number of factors can belie in vitro pharmacokinetic suggestion in human physiology, including not just individual differences in people themselves, but also significant differences in different versions of the ‘same’ naturopathic products. Therefore caution should still be observed. It should also be noted that in a clinical setting induction or inhibition of phase I or phase II enzymes, and by extension possible interaction with other medications, does not necessarily preclude use of these naturopathic medicines. Rather it implies that these factors should be taken into appropriate consideration when prescribing them and that the patient’s use of concomitant medicines should be routinely monitored (see the drug–CAM interactions table in Appendix 1).
In some instances dietary inclusion may be more beneficial than supplementation. Glutathione—a key nutrient in phase II metabolism of toxins—is best obtained from food sources, as many supplements may have limited bioavailability.36 Diets low in protein may predispose patients to lowered liver detoxification, as key amino acids are involved in these liver processes.91 Increasing crude protein intake will also help to improve availability of amino acid precursors to conjugation.
Detoxification
Modulation of intestinal microflora with probiotics and synbiotics (including dietary intervention with yoghurt) has also been demonstrated to improve the liver’s general function and detoxification ability in humans, most probably through the reduction of endotoxin load or ammonia production and resorption in the intestine.92–95
Exercise will also promote hepatic biotransformation processes.96,97 Fasting is also known to enhance the detoxification process,98 in part because the main source of energy is hydrolysed fatty acid tissue from adipose tissue stores, where many toxins are stored.99 However, due prudence needs to be displayed, as fasting may liberate toxins faster than they can be eliminated (because in part the adequate substrates from phase II detoxification may be missing or compromised) and may potentially endanger the patient.
Hydrotherapy is thought to increase filtration through the liver by encouraging blood circulation, in addition to aiding excretion through sweating.100 Sauna therapy has also been used to encourage elimination through the skin, with substantial elimination and significant clinical improvement thought possible through this mechanism.101,102 Sauna exposure of 5–15 minutes per day is safe and effective in enhancing detoxification, though caution is advised in patients with recent myocardial infarction or other serious cardiovascular complications, and patients need to be advised that eliminating toxins through the skin may initially irritate (though ultimately improve) conditions such as atopic dermatitis.103 Many nutrients—particularly trace elements such as zinc, copper, iron and chromium as well as electrolytes—may be lost through sweating and may need monitoring or replacement.
An Ayurvedic herbal formula consisting of Capparis spinosa, Cichorium intybus, Solanum nigrum, Terminalia arjuna, Cassia occidentalis, Achillea millefolium and Tamarix gallica has been found to stimulate liver detoxification in addition to exerting hepatoprotective properties.104
Some herbs have a history of use for detoxification and are used in traditional herbal medicine for their role in supporting liver function. Herbs traditionally labelled hepatics or ‘liver’ herbs including S. marianum, Cynara scolymus, Bupleurum falcatum, Schisandra chinensis, Peamus boldo and Taraxacum officinale) have also been used to detoxify wastes, including excessive hormones, and may also be considered.105–107
Detoxification may be of assistance to people with chronic, though not life-threatening, diseases. One study investigated the use of a nutrient supplement specifically targeted at supporting phase I and phase II detoxification mechanisms in 84 patients for 10 weeks, and found significant improvement in symptoms in the intervention group.108 The same product exhibited similar results in another trial as well as a 23% increase in liver detoxification as measured by caffeine-clearance tests.109 Other small or uncontrolled trials have also demonstrated improvement in nutritional and psychological symptoms, as well as excretion of toxic markers such as PCBs, following a detoxification regimen using high dose niacin, individualised vitamin and mineral supplementation and polyunsaturated oils combined with physical exercise and sauna therapy.110–112 Other more generalised integrative detoxification (that have not relied purely on high-level supplementation) programs have also shown improvements.113
Detoxification is also an area in which unproven and often ineffective remedies are aggressively marketed, both to practitioners and to patients, implying careful consideration before their use in clinical practice.114 Therefore, while detoxification regimens may provide a clinically valuable adjuvant to treatment, naturopathic practitioners should be sure to focus on more relevant primary treatment aims in the clinical setting. More extreme detoxification methods can be every dangerous and should be avoided. While it is true that many traditional methods may fall into this category, it should also be acknowledged that these traditions were borne of a time when environmental toxic burdens were far lower and would have resulted in fewer side effects and lower risk.