This is where an good percentage of the female population find themselves; with treatment refractory high blood pressure, that worsens across the menstrual cycle, during pregnancy and in response to certain formulations of oral contraceptives. Unbeknownst to many of these women and their doctors, they are carriers of a genetic mutation that raises their blood pressure relative to circulating progesterone concentrations. For these women, when progesterone concentrations are high, as during the luteal phase of menstrual cycle, and especially during pregnancy, blood pressure skyrockets uncontrollably. When progesterone concentrations are low and provided lifestyle variables are in check, blood pressure is more manageable.
Mineralocorticoids and Blood Pressure
Blood pressure is controlled in large part by what is called the mineralocorticoid system. This is a set of both steroid and peptide hormones that interact with the vasculature and the kidneys to increase or decrease blood flow. The mineralocorticoid hormone receptors are at the center of this system. Binding to these receptors is the mineralocorticoid hormone called aldosterone. Aldosterone regulates salt homeostasis and whether the kidneys store salt and water or release it.
Sensors within the kidneys monitor sodium concentrations. When there is not enough salt, they release the peptide hormones renin and then angiotensin I and II. The renin-angiotensin system then activates the release of the steroid hormone aldosterone. Aldosterone binds to the mineralocorticoid receptors and signals the kidney to reabsorb more salt. More water is also reabsorbed, and with those changes, plasma volume increases. Increased plasma volume, increases vascular volume which in turn requires a higher cardiac output. Increased cardiac output then leads increased blood pressure. The reverse is also true, decrease salt reabsorption and we get hypotension or low blood pressure.
Regulating Blood Pressure
At every junction there can be errors or mutations in this system and compensatory reactions to environmental or dietary changes. Add those possibilities to the variety of other factors that control blood pressure (baroreceptors, natriutetic peptides, kinin-kallikrein, adrenergic receptors, nitric oxide and endothelin) and it is easy to see why hypertension is sometimes difficult to manage. Women, however, have the added bonus of constantly changing hormone concentrations, across the menstrual cycle, pharmaceutically, across pregnancy and across menopause. Since the mineralocorticoid receptors, like all steroid hormone receptors, bind promiscuously to a bunch of different hormones, it is easy to see how drastically changing hormone concentrations can impact salt and water homeostasis (premenstrual swelling, pregnancy swelling, oral contraceptive swelling), and ultimately, blood pressure. Add a little stress to this mix and we have a recipe for hypertension. Indeed, it should be noted that both cortisol, the stress hormone, and progesterone, bind more strongly to the mineralocorticoid receptor than aldosterone.
Progesterone Binds to Mineralocorticoid Receptors
Progesterone, the reproductive hormone that prepares the endometrium for implantation during the luteal phase of the menstrual cycle and supports the pregnancy once underway, binds to mineralocorticoid receptor. The relationship between progesterone and blood pressure is complex, but mostly progesterone blocks the mineralocorticoid receptors and lowers blood pressure. In some women, however, the shape of the mineralocorticoid receptor is altered, allowing for increased progesterone binding in such a way that it activates the signals sent from the receptor. So rather than block the mineralocorticoid-aldosterone pathway, it launches it. Progesterone then becomes the conduit for increasing salt and water retention and increasing blood pressure.
Progesterone and High Blood Pressure
For women who carry this gain-of-function mineralocorticoid receptor mutation, high blood pressure emerges early, before the age of 20 and, for all intents and purposes, is refractory to the normal lifestyle changes and many medications that reduce blood pressure, except perhaps diuretics. The high blood pressure often becomes severe during pregnancy. It may also become severe with any drug that increases progesterone or decreases aldosterone including with oral contraceptives, synthetic progestins (medroxyprogesterone, micronized progesterone, prempro and related), and blood pressure medications that block aldosterone (spironolactone) and are derived from 17a- spirolactone. Fourth generation progestin, contraceptives or hormone replacement therapies (HRT) containing drospirenone are particularly dangerous, as they both bind to progesterone receptors strongly and block mineralocortiocoid activity simultaneously.
It should be noted that boys and men also carry this mutation and are susceptible to early onset hypertension.
The Problem with Progesterone Mediated Blood Pressure
The problem with progesterone mediated high blood pressure is one of recognition. High blood pressure in general is not recognized in young women. Blood pressure mediated by progesterone concentrations, whether via endogenous and menstrually-related changes or the use of synthetic progestins, is all but completely unrecognized. Genetic testing in this population is unheard of. Consequently, many young women are at risk for cardiac and thromboembolic events and do not know it. Could the sudden deaths reported in association with drosperinone oral contraceptives be related to unrecognized gain of function mineralocorticoid mutations? Possibly.
During pregnancy, the risk is magnified exponentially as progesterone concentrations increase several hundred fold. Hypertension accounts for 6% of all pregnancy complications, one wonders what percentage are related to progesterone? No one knows, because it is not studied.
For older women, though blood pressure is routinely monitored, connections between synthetic progestins in HRT and blood pressure elevations may only be cursorily understood, leaving many women open to inadvertently increasing their risk for heart attack and stroke coincident with attempts to manage menopausal symptoms. Although, hormones naturally decline during menopause, the re-supplementation of progesterone and progestins can be problematic for these women.
Fourth Generation Progestins: The Dangers of Drospirenone
For women with the gain of function mutation, certain forms of oral contraceptives and HRT can be deadly. The 4th generation progestins contained the Yas, Yasmin, Ocella series of birth control pills and in the Angeliq brand of HRT, are derived from a synthetic progestin that blocks the mineralocorticoid receptor directly.
Drospirenone is a progestin and mineralocorticoid antagonist derived from 17a- spirolactone. 17a- spirolactone blocks aldosterone. Under normal circumstances, blocking aldosterone’s ability to bind with mineralocorticoid receptors might be a good thing and reduce high blood pressure, particularly in folks who have aldosterone based hypertension or who are in heart failure. In other populations, however, blocking aldosterone might not be such a great idea.
Drospirenone based oral contraceptives and HRT formulations contain progestins that bind with equal affinity to the progesterone receptor compared to endogenous progesterone, but bind 500X more strongly to the mineralocorticoid receptors than aldosterone. This is problematic for most women, even if they don’t carry the gain-of-function mutation. Drospirenone based contraceptives increase the rate of serious cardiovascular events by as much as 6X compared to the older contraceptives. In women who carry the gain of function mineralocorticoid receptor mutation, taking a drosperinone based oral contraceptive or menopausal replacement therapy, the results can be deadly.
Drospirenone – Mineralocorticoid Receptor Connection
If one has the gain of function mutation, where the mineralocorticoid receptors preferentially bind with progesterone and its metabolites, blocking what remaining aldosterone controlled feedback loops of salt/water balance, skews the receptor activity in such a way that it is always on, and always telling the kidneys to reabsorb more salt and water. Similarly, increasing progesterone concentrations unnaturally, with drosperinone, or any other progestin, quantitatively increases binding with the mineralocorticoid receptors, displacing aldosterone, removing important feedback controls and creating a state of perpetual progestin-mineralocorticoid activation.
Epigenetic Factors in Blood Pressure
Environmental toxicants and pharmaceuticals induce what are called epigenetic changes in protein expression. Epigenetic means beyond genetics. These types of changes don’t alter DNA per se, just alter whether a certain protein codes are activated or deactivated. There are number technical mechanisms by which epigenetic variables can alter receptor expression and function. For other receptors, especially the glucocorticoid and estrogen receptors, many of these epigenetic mechanisms have been elucidated. Not so for the mineralocorticoid receptors. Certainly, with environmental exposures, which are all endocrine disrupting in some manner or another, it is possible to create constitutively open mineralocorticoid receptors, much like the gain of function mutations. This would mean that millions of women could be a great risk when using drospirenone based oral contraceptives or HRT, progesterone increasing or mimicing drugs (most oral contraceptives and HRT), aldosterone blocking agents from spirolactone and during pregnancy. Even across the menstrual cycle, blood pressure would be expected to wax and wane relative to circulating progesterone concentrations.
Maybe it is time to move beyond the one hormone, one receptor, one function view of endocrinology. It’s certainly time to address the role of cycling hormones on human physiology. Cycling progesterone concentrations impact blood pressure; recognizing this simple fact would help women and their physicians develop more reasonable and effective approaches to managing high blood pressure.