UPDATE--Evidence-based analysis of progesterone and MPA effects on the heart will appear in the July 2008 issue of Nature Clinical Practice Cardiovascular Medicine. The peer-reviewed publication of "Cardiovascular effects of medroxyprogesterone acetate and progesterone: a case of mistaken identity?" is now listed on the NCPCV website Advance Online Publication page (URL = www.nature.com/ncpcardio/journal/vaop/ncurrent/index.html).

The contribution to recognition of refractory angina pectoris that is predominant in women was written by R Kent Hermsmeyer, Theresa L Thompson, Gerald M Pohost, and Juan Carlos Kaski. Publication in print is expected to occur in the July 2008 issue.

The misunderstanding that the word "progesterone" might be a class of steroid compounds (as might be logically supposed because "estrogen" is the word meaning the whole class of estrogenic steroids) is a source of confusion. Progesterone is a single, specific chemical molecule. The words that should be used to refer to progestagenic compounds as a group are in fact "progestin" and "progestagen" (which are, by the way, synonymous) and "progestogen" (an alternative spelling). The synthetic progestin, medroxyprogesterone acetate (MPA), also known as Provera, Depo-Provera, and incorporated as the progestin in Prempro and Premphase (the most commonly prescribed USA postmenopausal hormone therapies), is a distinctly different chemical entity with biological actions on blood vessels very unlike the actions of progesterone.

Progesterone is an endogenous (naturally occuring) human hormone for which important beneficial gene level actions--previously unrecognized--have been discovered, and for which a threshold for normal function has been defined.

Yet progesterone is blamed, due to the misunderstanding but without evidence, for the sins of MPA.

The confused terminology is so pervasive that investigations of potential beneficial functions of progesterone have not been carried out, and thus the progress greatly delayed in answering fundamental questions related to the notion of essential roles of progesterone. Notice the 2004 Missmer reference as an example. MPA was designed as a synthetically altered derivative of progesterone to allow convenient oral dosing and improved duration of action (as the half-life of bio-identical progesterone is only a matter of minutes). The indication for use tested was the secretory transition in endometrium of the uterus. Other actions (on blood vessel function, blood clotting, and breast cancer) were not adequately tested.

Non-oral formulations of safe, bio-identical steroids, introduced through the skin at low doses over many hours (as patches or creams), provide a more rational approach. The short half-life problem is overcome, the extensive metabolism by the liver is avoided, and many side effects are minimized or eliminated by using transdermal progesterone. The lower (than in a normal cycle) dose of transdermal progesterone used in Dimera research is now in Phase III FDA human clinical trials.

Serotonin, 5-hydroxytryptamine, 5HT

Serotonin is one of the important vasoconstrictor substances that is stored at very high (potentially lethal) concentrations, and released from activated blood platelets upon injury causing local vasoconstriction at the site of a blood vessel tear or cut. The clamping off of the damaged blood vessel assists with limiting the loss of blood.

Thromboxane A2

Thromboxane A2 is another substance found at very high concentrations in blood platelets and released upon platelet activation to produce strong, prolonged vasoconstriction locally at the site of injury, ruptures, or cuts, of a blood vessel to limit blood loss. Thromboxane A2 has a short half-life in blood (only a few seconds), but may form or trigger release of longer lasting persistent vasoconstrictors. Serotonin and thromboxane A2 are synergistic, amplifying the combined effect to be greater than the sum.

Ovariectomy

Ovariectomy is surgical removal of the ovary, and usually performed as bilateral ovariectomy (removing both left and right ovaries). As the ovary is an important source of estrogens and in practical terms the only source of progesterone in non-pregnant women, this surgically induced menopause procedure (if pre-menopausal) removes a complex and poorly understood source of important hormones that have actions on the heart, blood vessels, brain, bones, pituitary, immune system, and perhaps other important targets in addition to well-known actions on the urogenital system. Dimera research has the aim of finding effective therapies to replace those effects of ovarian steroids that are beneficial without introducing adverse actions.

Artery Reactivity

Dimera has discovered and developed the concept of blood vessel hyperreactivity. In addition to plaques or clots that can block blood flow by physical obstruction, there can also be functional reasons for prolonged impaired blood flow (ischemia). Blood vessels function by dynamically constricting and relaxing to regulate blood flow. The heart, brain, and kidneys require nearly constant high blood flow while other areas, e.g., skin, skeletal muscle, and stomach, need higher blood flow for only short periods on demand. Constriction and dilation of blood vessels occurs as the vascular muscle of the blood vessel wall contracts or relaxes to allow distributed regulation of blood flow. Blood circulates in people in a network of blood vessels that is capable (if dilated) of containing more than 3 times that volume, and thus is highly dependent on a state of constriction (called vascular tone). The blood flow to each organ is locally determined by vascular tone, which is organ specific and changing from moment to moment. The sum of the time averaged composite resistance of all blood vessels consequently determines blood pressure. Imbalances that occur during aging can cause malfunctions of the multiple regulatory mechanisms that insure blood supplies to vital organs. Blood flow demand by running legs might, for example, conflict with those of the stomach when digesting. More serious problems would develop if demand by running legs diverted necessary blood from the heart.

Subtle but important deficiencies in blood flow can therefore result from an imbalance of vasoconstrictor or vasodilator responses to everyday situations. Disturbances in the balance of multiple normal constrictor and dilator influences are the basis for the concept of abnormal vascular reactivity. In the case of a pure reactivity explanation, there would be no structurally detectable indication of a problem, diagnosis would be more difficult, and the cause would be more of a puzzle. Because the abnormality can only be recognized when observed in action (such as when provoked by injection of vasoconstrictors in the cardiac catheterization laboratory), this mechanism is elusive, requiring multi-factorial knowledge of when and how to document unpredictable transient malfunctions. Due to issues of cost and limited facilities, dynamic measurements are presently feasible in only about 1% of those who may benefit. Reactivity increases presently detectable in the catheterization laboratory as slow flow, prolonged TIMI counts, or prolonged disappearance of major coronary arteries from angiograms are only caught under a challenge, and even then influenced by chance. Advances in cardiac diagnostic technology are promising to open important windows of opportunity to detect dynamic causes of ischemia (blood flow deficit) using high strength magnetic resonance (MR). Microvascular deficits are possible to detect with such sophisticated MR approaches. With high resolution MR (which is non-invasive and does not require any radiation), a concept is emerging that appears promising to explain the unaccounted for and less obvious causes of coronary ischemia that cause angina pectoris and cardiac symptoms. Patients in this group may have previously been categorized as "normal," or with reference to no structural evidence from angiography (and thus a negative evaluation) for those who had angina (positive evaluation) as the limiting symptom during the Treadmill Exercise Test (electrocardiogram), as " false positives."

Artery reactivity increases defined by prolonged vasoconstriction are hypothesized by Dimera to be major, even though previously unappreciated, causes of ischemia and related serious illness that may allow more enlightened definitions of blood vessel pathophysiology and treatment.