Grip Strength – Are You Underutilizing This Predictor of Aging and Health?
This article was written with Romilly Hodges CNS.
Insulin resistance, excess weight, fatty liver, infertility, and elevated androgen levels – these are clinical features common to two conditions that we wouldn’t necessarily think to connect: polycystic ovary syndrome (PCOS) and hemochromatosis.
Interestingly, excess iron is a common finding in BOTH conditions.
A new patient of mine – we’ll call her Anne – recently presented with PCOS along with mildly elevated iron levels. In this blog, I tease out the relevance of this, especially in the context of emerging research on the connections, and explain how I put those considerations into the development of her treatment plan.
I have also covered functional medicine considerations for PCOS in a previous case report, which you may also wish to refer to. A search for “PCOS” on this site will also give you additional information resources.
Overlaps between PCOS and hemochromatosis, and the implications of excess iron
Hemochromatosis is caused by single-gene mutations, seemingly a far cry from the multifactorial etiology of PCOS. Despite this, there is a surprising overlap in the clinical presentation of both conditions:
Common findings possible in both PCOS and hemochromatosis:
- Type II diabetes
- Insulin resistance
- Dyslipidemia
- NAFLD
- Increased risk for breast cancer
- Pituitary dysfunction
- Infertility
- Adiposity
- Abnormal skin pigmentation
- Iron excess (mild in PCOS, can be much more severe in hemochromatosis)
- Oxidative stress
It may be tempting to say that excess adiposity explains most of these clinical features. But it would be remiss to ignore the bidirectional relationships between iron regulation and metabolism. Manipulation of iron regulation and status has been shown to affect glucose and lipid metabolism. Evidence suggests that “iron accumulation and metabolism may play a role in the development of metabolic diseases including obesity, type 2 diabetes, hyperlipidaemia and non-alcoholic fatty liver disease.”
In fact, one of the first characterizations of insulin resistance was in 1929 as “bronze diabetes,” in reference to the deep reddening of the skin that can occur in poorly managed hemochromatosis. Several studies have found associations between excess iron and metabolic dysregulation and prospective studies have suggested a causal relationship. In a large study of over 28,000 participants, higher levels of ferritin and transferrin predicted the development of type 2 diabetes. And in animal studies, high-iron diets result in increased insulin resistance (higher fasting glucose, higher triglycerides). Iron levels can affect glucose regulation, thermoregulation, appetite, leptin, and thyroid function, and the link between iron and metabolic disease is well-established at this point. The relationships are complex, however, and mechanisms are not fully understood.
Iron-related enzymes/transporters altered in PCOS
Iron transport and metabolism systems are regularly found to be altered in PCOS.
Ferritin
Ferritin is the iron storage protein found in cells. Ferritin increases when iron is present in excess amounts (although it can also rise during inflammation or infection, which is what also makes ferritin an acute phase reactant). Its role is to reduce the oxidative potential of excess iron levels by sequestering Fe2+ in its less reactive form – Fe3+. Serum ferritin levels are often increased in patients with PCOS, suggesting a mild iron overload and/or inflammation.
Haptoglobin
Haptoglobin is a plasma protein with a high binding affinity for hemoglobin (the protein in red blood cells that carries oxygen). When haptoglobin binds to hemoglobin, it triggers the liver to clear that hemoglobin from the blood. Some research has shown that haptoglobin levels are significantly reduced in PCOS in a manner correlated with disease severity. A common SNP in the gene coding for part of the haptoglobin molecule is also associated with PCOS and is associated with reduced production of haptoglobin.
When haptoglobin levels are lower, there are higher than normal levels of free hemoglobin in circulation. The excess heme (within the hemoglobin molecule) is taken up by macrophages and degraded, releasing iron. Therefore, lower levels of haptoglobin can lead to higher iron levels.
Another mechanism that’s triggered by higher levels of free hemoglobin is increased expression of ferroportin, the iron exporter on the basolateral membrane of enterocytes. The net effect of this change is increased dietary iron uptake from the intestine.
Not least, haptoglobin itself has antioxidant and anti-inflammatory properties. So less haptoglobin means less to counter the pro-oxidant effects of excess iron.
Hepcidin
Hepcidin is an important iron-regulatory hormone. It acts by binding to ferroportin transporters on both enterocyte and macrophage membranes and initiates its degradation. The effect is to reduce iron uptake from the intestine and release from macrophage cells – both reduce iron in circulation.
Some (though not all) studies have found a reduction in plasma hepcidin in PCOS patients, suggesting that it may play a role in select PCOS cases. However, decreased hepcidin is not universal in PCOS.
Iron-related toxicity and relevance to clinical presentation
The molecular mechanism of iron toxicity in the body is as a potent oxidant. Iron-induced oxidative stress includes:
- The Fenton reaction, generating highly reactive hydroxyl radicals.
- Activating NADPH oxidase, increasing the generation of superoxide radicals.
- Degrading glutathione peroxidase, resulting in decreased antioxidant capacity.
- Upregulating NF-kappaB, a “master pro-inflammatory switch.”
- Upregulating iNOS increasing nitric oxide synthesis.
Increased nitric oxide has been known for some time to inhibit aromatase activity in the ovary’s granulosa cells. This is thought to perhaps explain the excess production of androgens in ovaries when they are exposed to excess iron.
It’s also worth mentioning here that iron toxicity has also been recently related to some instances of Alzheimer’s disease and vascular dementia.
Iron-related lab findings in PCOS
Excess iron is considered a universal finding in PCOS. However, the iron overload is typically only mild (a point of divergence from the typically more extreme iron overload in hemochromatosis). Iron biomarker findings tend to be heterogeneous, reflecting the variable etiology and presentation of PCOS across patients.
In Anne’s case, the only abnormal iron finding was a high transferrin saturation. However, this can be an early indication of overload. Her ferritin was only 16, which is right at the lower end of normal and would not have flagged me to paying attention to iron without the whole panel of iron markers. The additional information from those extra analytes definitely informed my decision making.
Therapeutic considerations
Phlebotomy
Just as in hemochromatosis (where regular phlebotomy is widely used to control iron levels), phlebotomy can be therapeutically relevant in PCOS.
Clinical trials have shown the effectiveness of phlebotomy in PCOS patients. One RCT showed phlebotomy is comparable to oral contraceptive therapy at reversing insulin resistance and hyperandrogenemia and had fewer negative effects on triglycerides (although the oral contraceptive intervention was more effective at treating menstrual disturbances). However, other trials have found no benefit of adding phlebotomy on insulin sensitivity or oxidative stress in patients who were already on combined oral contraceptives, which are known to have potentially pro-oxidant effects.
Microbiome
Dysbiosis is a clinical feature of PCOS (as well as hemochromatosis) and may be a relevant factor in how much iron is absorbed into circulation. Lactobacilli present in the digestive tract have been shown to correlate with estrogen levels. Additionally, it has been demonstrated in animals that fecal microbiota transplants can reduce androgen levels and improve estrogen cycles. Not least, the lower concentrations of SCFAs found in PCOS patients may play a role in insulin resistance and diabetes.
There are four known metabolites produced by beneficial gut bacteria (L. reuteri and L. rhamnosus GG have been identified as producers, although there may be others) that have a net effect of reducing intestinal iron absorption. Overall, a meta analysis of studies using probiotics in PCOS patients indicates the potential for microbiome-targeted interventions to improve weight, insulin resistance, lipids, inflammation, hyperandrogenemia, and oxidative stress.
Nutrients
Uptake of iron from the intestine occurs via divalent metal transporters (DMTs), which are also used by other divalent minerals – magnesium, calcium, and zinc. Those minerals will compete with iron for absorption and so ensuring their repletion is a reasonable strategy to reduce intestinal iron uptake.
Building a treatment plan for Anne
In Anne’s case, the presence of high transferrin saturation was an early sign of iron overload, so I did test her genetics and found she was positive for 2 copies of HFE gene variant found in type 1 hemochromatosis. This means that we need to keep an eye on her iron numbers. Regardless of the provider she’s working with she should always request a full iron panel rather than just a ferritin which, as I mentioned above, can be misleading. Overall, her labs didn’t warrant starting phlebotomy at this time – it’s her menses that will be controlling iron levels while she’s premenopausal. However, I did start her on a gut-centric protocol with probiotics and an iron-free multimineral. A low-glycemic and high-antioxidant diet was also part of her plan, along with moderate exercise. We’ll be keeping a close eye on her iron values as we continue our work together.
The other really important thing (and I discuss this in a previous iron overload case) is that toxic metals will hitch a ride on those DMT transporters as well. HFE-loss gene mutations are associated with an increased expression of DMT transporters (which are present at the blood brain barrier, not just in the intestines). Lead, mercury, cadmium, arsenic and even manganese. Honestly, one of the MOST valuable pieces of information to have from testing the HFE genes is to see whether we need to be watching for toxins – we want to monitor toxin levels at least annually in anyone with the genes. Whole blood levels at a minimum. In Anne’s case, even as her regular cycles are largely addressing her potential for excess iron levels, toxic metals still need to be monitored.
Finally, as we explore iron levels, we want to keep an eye on the complete blood count…to make sure RBC indices are within normal limits also. We can see changes here with anemia, obviously, but also with iron overload we can see these values rise sometimes. So it’s just useful to review periodically and confirm all is fine.
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Great information and I just learned so much.
Thank you!