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Adipose Hormones
It is important to understand that immune system function depends on metabolic health and that obesity is a predisposing risk factor for RA and SLE. Adipose is not an inert substance; it can make inflammatory cytokines such as TNFa, IL-1 and IL-6, and a class of molecules termed adipokines. Adipokines are proteins made by fat that are highly biologically active. The adipokines that have been best characterized in RA and SLE are adiponectin, leptin, and visfatin, all of which are increased compared with matched controls.
Leptin signals satiety in the hypothalamus but also has receptors on NK cells, T and B cells, and monocytes and can act similarly to inflammatory cytokines on these cells. Increased circulating leptin is associated with many inflammatory diseases such as inflammatory bowel disease, SLE, RA, type 1 diabetes, Behcet's disease, and Graves'. Leptin is higher in women than men, further elucidating the female predominance of SLE and RA.
Adiponectin is an adipokine made by metabolically "healthy" fat. Most research has focused on the antidiabetic and antiarthrogenic activity of this hormone. In SLE and RA, adiponectin is elevated, which may be a compensatory mechanism that is trying to balance the elevated leptin and visfatin, which are increased over matched controls.20,21 It has been speculated that in the presence of inflammatory disease, higher adiponectin may not be desirable because it may in fact become pro-inflammatory and release prodegradative enzymes such as matrix metalloproteinases (MMPs) and nitric oxide in chondrocytes.22
Of all the adipokines studied in RA, elevated adiponectin is the best predictive marker for joint destruction. If adiponectin is low at the onset of disease, this has high negative predictive value for disease progression.22
Testing and Treatment
With a deeper understanding of the patterns of hormonal dysfunction in rheumatoid arthritis and SLE, we can turn our attention to diagnosis and treatment. There are many options available for hormone testing. Sex and adrenal hormones are best assessed through urine or saliva testing and adipokines via serum. A 24-hour urine test can easily assess estrogen metabolism (2-, 4-, 16-hydroxyestrones), total estrogens, androgens, cortisone, cortisol, and DHEA. The only drawback of a 24-hour urine collection is that it does not assess the diurnal pattern of cortisol release. This can be assessed with either saliva testing or dried urine spot testing for hormones. The dried urine spot testing offers the benefit of estrogen metabolism and diurnal cortisol patterns in one test and can be used to assess hormones in patients treated with sublingual hormone therapy.
Adrenal Hormones
There are many possible benefits of treating adrenal hormone dysfunction in RA and SLE patients. Quality of life; disease activity; and improving side effects from glucocorticoid treatment such as the increased risk of infection, osteoporosis, and myopathy have all been evaluated, with positive outcomes.23-29
Treatment of adrenal hormone imbalances should always start with the basics of establishing strong routines and stress management techniques. Many adrenal herbs are also immunomodulating and should be used cautiously only in stable RA and SLE patients. These include but are not limited to Withania somnifera, Glycyrrhiza glabra, Eleuthrococcus senticosus, panax spp., Cordyceps sinensis, and Rhodiola rosea.
Adrenal hormone replacement therapy is often well tolerated, and a number of different delivery forms are available. If a patient has a cortisol and DHEA deficiency, it is important to provide replacement for both, as DHEA only replacement can cause a worsening cortisol deficiency. One option for patients deficient in both is pregnenolone, dosed between 25 and 100 mg per day. Most female patients will tolerate DHEA dosed under 50 mg without getting symptoms related to overconversion to androgens. Recall that many of these patients are androgen deficient and it is common that DHEA alone can address both hormone deficiencies. If patients develop acne, increased hair growth, or anger issues, 7-keto-DHEA is a good option.
Cortisol deficiency can be addressed with hydrocortisone (Cortef) at subphysiological dosing (<20 mg total per day) or standardized adrenal glandular. If pregnenolone is used for dual replacement, it is important to assess if it is well metabolized with either urine or saliva testing.
Androgens
Androgen deficiency can be caused by an overexpression of the aromatase enzyme. Aromatase converts DHEA to estrogens rather than testosterone. It is upregulated by inflammatory cytokines such as TNFa, IL-6 and IL-1, and adipokines. The aromatase enzyme can also be inhibited with many integrative interventions. Turnera diffusa (damiana) has been used in traditional botanical medicine as an aphrodisiac, and now studies have shown that the constituents pinocembrin and acacetin have strong antiaromatase activity.30 Scutellaria spp. also have antiaromatase activity, and could be a good choice of therapy in patients who have concomitant anxiety.31
Dietary polyphenols can inhibit aromatase and decrease inflammatory mediators produced by adipose tissue. Resveratrol, curcumin, and epigallocatechin gallate (EGCG) have been well studied for in vivo antiaromatase activity.32 If patients are using red wine as a source of resveratrol, it is very important to emphasize moderation because the alcohol will decrease liver metabolism of estrogens. This effect has been studied in red wine, and the strength of aromatase inhibition is stronger than the alcohol effect on the liver processing if intake is limited to 2 glasses per week.33
Borrowing from the hormone sensitive cancer research, we have also learned that melatonin can also modulate aromatase activity, highlighting the importance of healthy sleep/wake cycles.34 Basic sleep hygiene includes going to bed at the same time each night, sleeping in the pitch black, avoiding all screens for 2 hours prior to sleep, and exposure to natural light within 30 minutes of waking.
In the face of overt inflammation, aromatase inhibition alone may not be sufficient to correct the androgen deficiency seen in RA and SLE. Many patients benefit clinically from hormone replacement therapy with testosterone. Testosterone cannot be delivered orally and must be given in a topical preparation (absorption is highly variable), sublingual troche, or implanted trocar. A reasonable starting dose of sublingual troche is 5 mg, titrated up/down based on labs and symptoms.
Estrogen
First and foremost, patients must be strongly counseled to avoid xenoestrogens. Table 4 provides an abbreviated list of sources and types of xenoestrogens. Encouraging patients to switch to an organic diet and avoiding plastics in food storage is an important first step. One study found that switching to organic foods can drop the level of organophosphate pesticides in the blood by 89% in one week.35
Table 4: Common Xenoestrogens
Pesticides Plastics
atrazine bisphenol A
organochlorines bisphenol S
Cosmetics Estrogen Contraception
phthalates oral
parabens patch etc
Dry cleaning Water pollution
Dairy products Meat products
Estrogen metabolism defects can be well managed with dietary changes and nutraceutical interventions. 3,3'-diindolylmethane (DIM) is a compound found in cruciferous vegetables that has been well studied in breast, cervical, and thyroid cancers for its antiestrogenic, positive estrogen metabolism effects. DIM strongly influences estrogen metabolism to help favor 2-hydroxyestrone.36-39 Patients should be encouraged to eat at least 2 cups of cruciferous vegetables per day, and if the ratio of urine 2:16 OH-estrone is less than 2, DIM should be given. Reasonable dosage range for DIM is 200 to 600 mg per day in divided doses. The ideal diet also includes high-flavonoid foods such as green tea, fruits, and vegetables to encourage healthy estrogen metabolism.40
Prolactin
If prolactin is elevated, Vitex angus is a very good option for treatment.41,42 Vitex can have the collateral benefit of increasing luteal phase progesterone levels that may benefit symptoms. Hyperprolactinemia can also be addressed via dopamine agonism. While the prescription medication bromocriptine is an option, tyrosine supplementation or Mucuna pruriens can also be effective dopamine agonists.43-45
Adipokines
It is beyond the scope of this review to fully discuss methods to modulate adipokines and improve metabolic health. For patients with RA and SLE, metabolic health can benefit from short-term fasting, exercise, and improvement in sleep cycles. In RA patients, fasting appears to increase Treg cells and induce CD4+ lymphocyte hyporeactivity.46 Adequate sleep can decrease circulating leptin levels.47 From a dietary perspective, increasing protein levels to 30% of caloric intake and limited carbohydrates can also improve elevated leptin.48
All patients should be encouraged to have a minimum 12-hour fast between dinner and breakfast. For motivated patients, a once-weekly longer fast between 14 and 24 hours may be highly beneficial. The metabolic and immune benefits of intermittent fasting are currently being studied in rheumatoid arthritis as well as many other diseases.49
Increasing physical activity can also decrease leptin, as well as inflammatory cytokines.50 There are many options for increasing physical activity. One form of exercise that has been well shown to improve leptin is high-intensity interval training; however, patients with active joint disease may not tolerate this form of exercise training, in which case water-based therapy or pedometer activity tracking can be used.
Conclusion
To date, no one has researched the clinical impact of simultaneously addressing adrenal, sex, and adipose hormones in RA and SLE. In my experience, treating hormones is absolutely fundamental to obtaining remission without the use of pharmaceuticals and can be that "magic piece" after dietary changes, microbiome modulation, gut healing, and aggressive anti-inflammatory strategies have failed to adequately manage symptoms. Table 5 provides a summary of recommendations. Assessment and appropriate treatment can also minimize side effects and minimize dosage of conventional DMARD therapy. Not only can appropriate hormone treatment affect disease activity, it can also substantially improve quality-of-life measures such as mood and energy, for which your patient will be very grateful.
Table 5: Summary of Recommendations
Adrenal Hormones
Stress management
Adrenal glandulars
Hydrocortisone |
Establish routines
DHEA
Caution with adrenal-stimulating herbs |
Androgen Support
Dietary polyphenols
Melatonin
Scutellaria spp.
Testosterone replacement |
Dietary flavonoids
Turnera diffusa
DHEA
Sleep hygiene |
Estrogen Support
Avoid xenoestrogens
Diindolylmethane
Weight loss |
Dietary flavonoids
Dietary cruciferous vegetables
Luteal phase progesterone replacement |
Prolactin Support
Vitex angus
Mucuna pruriens |
Tyrosine |
Adipokine Support
Short-term fasting
Low-carbohydrate diet
Optimal sleep cycles
|
Weight loss
Exercise
Protein 30% |
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