Biology of Raynaud’s Phenomenon
Primary Raynaud’s Phenomenon
Although the causes(s) of primary Raynaud’s phenomenon are not entirely understood, a significant underlying feature appears to be an abnormal response of alpha-2 adrenergic receptors, which are proteins on cell surfaces that bind to hormones like norepinephrine and epinephrine and help control the stress response, regulate blood pressure, and control heart rate. Alpha-2 adrenergic receptors are particularly abundant within the blood vessels in the fingers, and their abnormal response can cause vasoconstriction (Herrick 2012). This process occurs in response to cold or emotional stress, and may be driven in part by free radicals, which cause oxidative stress (Boin 2005; Herrick 2012).
Oxidative stress is implicated not only in the pathogenesis of Raynaud’s phenomenon, but can be a significant consequence of the ischemia-reperfusion characteristic of both the primary and secondary forms of this disease as well. Lack of blood flow (ischemia), and its subsequent return (reperfusion), generates free radicals, which can damage the delicate interior lining of the blood vessels, called the endothelium, in the affected tissues; in severe cases this may lead to ulcers and tissue death. Therefore, antioxidants, which neutralize free radicals, have received significant attention among researchers studying Raynaud’s phenomenon (Herrick 2012).
Secondary Raynaud’s Phenomenon
Other biologic and chemical pathways are thought to be involved in secondary, and possibly also primary, Raynaud’s phenomenon. These include (Cooke 2005; Herrick 2012):
Vascular abnormalities. A key feature of secondary Raynaud’s phenomenon is a disruption of the vasodilation/vasoconstriction equilibrium, resulting in decreased vasodilation and increased vasoconstriction (Roustit 2011; Herrick 2012). This appears to be a consequence of decreased production of chemicals that dilate blood vessels, combined with the increased production of chemicals that constrict them (Herrick 2012).
In primary Raynaud’s phenomenon, structural abnormalities are thought to be subtle, and the vascular defect is mostly functional (Herrick 2005). On the other hand, in secondary Raynaud’s phenomenon blood vessels have several structural and functional abnormalities (Herrick 2011).
Various blood vessel abnormalities observed in secondary Raynaud’s phenomenon occur as a consequence of an underlying connective tissue disease, such as systemic sclerosis. These include enlarged, widened capillaries through which blood flow is sluggish. One of the most significant changes appears to be the increased thickness of the endothelium. Other contributors to vascular damage include the apoptosis, or programmed cell death, of endothelial cells; abnormal expression of transcription factors, which are proteins required for normal genetic processes; aberrant production of inflammatory cytokines; and irregularities in angiogenesis, which is the production and growth of blood vessels (Herrick 2012).
The endothelium, or the inner lining of the blood vessels, is a very dynamic structure that not only produces vasoactive chemicals, but also reacts to their presence. Some of these chemicals dilate, while others constrict the blood vessels (Herrick 2005). One aspect of Raynaud’s phenomenon that is not yet completely understood is whether the production of these vasoactive chemicals is impaired, or the endothelium does not respond to them properly (Herrick 2012).
One such vasoactive chemical that has received intense scrutiny in the context of Raynaud’s phenomenon is nitric oxide (NO). There are several forms of nitric oxide synthase (NOS), the enzyme that produces nitric oxide; in secondary Raynaud’s, some forms are overexpressed and others are underexpressed, complicating a clear understanding of nitric oxide’s role in the condition. Both increased and decreased nitric oxide production were reported in various studies, and the overall effect of NO in this condition was referred to as “paradoxical”, because it has positive as well as negative components (Matucci Cerinic 2002). Nonetheless, studies show that applying topical nitroglycerin, a compound that increases nitric oxide generation, provokes vasodilation in both primary and secondary Raynaud’s phenomenon and may relieve symptoms (Herrick 2012).
Additional contributing factors. Aside from factors directly related to the structure or function of the blood vessels, several intravascular factors have also been implicated in the pathogenesis of secondary Raynaud’s phenomenon (Herrick 2005). These include increased white blood cell and platelet activation, defective blood clotting, and increased blood viscosity (Herrick 2005, 2012). Neural abnormalities may be implicated as well. Nerve endings in the skin release chemicals called neuropeptides in response to various stimuli from the environment. The biological cascade they trigger can also result in the constriction or dilation of the blood vessels (Herrick 2012).
The Potential Role of Hormones in Raynaud’s Phenomenon Among Women
Hormonal factors, particularly estrogen, may also play a role in the etiology of Raynaud’s phenomenon among women. The relationship appears to be complex, however, as some studies suggest estrogens promote vasodilation in Raynaud’s phenomenon, whereas others point to a vasoconstrictive effect (Herrick 2012).
There is some evidence that estrogen replacement therapy (without progesterone) may be associated with Raynaud’s phenomenon. In a study that enrolled 49 women, Raynaud’s phenomenon was present in 19.1% of women receiving estrogen, 9.8% of women receiving estrogen together with progesterone, and 8.4% of women not receiving any estrogen (Fraenkel 1998). These observations are supported by the finding that estrogen increases the production of alpha 2C-adrenergic receptors, which play a role in vasoconstriction (Kleinert 1998; Eid 2007). On the other hand, progesterone has been shown to mitigate vasoconstriction and promote vasodilation, suggesting the observed vasoconstrictive tendencies of estrogen in Raynaud’s phenomenon may be offset if levels of the two hormones are balanced (Thomas 2013).
Although more studies are needed to firmly establish the role of estrogen and progesterone in Raynaud’s phenomenon, women affected by Raynaud’s are encouraged to have a blood test to assess their sex hormone levels. If an imbalance is detected, then women can work with a physician experienced in bioidentical hormone replacement therapy to naturally restore hormonal balance. More information is available in the Female Hormone Restoration protocol.