This is the main source of circulating pyrophosphate (PPi), and individuals affected by PXE have strongly reduced plasma PPi levels, explaining their mineralization disorder. One study suggested that mutations causing total absence of an ABCC6 protein caused a more severe disease, but this could not be confirmed in a subsequent case series. Given the variations in age of onset and severity it is likely that other unknown risk factors (genetic, environmental, and lifestyle) may be involved.Premature atherosclerosis is also associated with mutations in the ABCC6 gene, even in those without PXE. A syndrome almost indistinguishable from hereditary PXE has been described in patients with hemoglobinopathies (sickle-cell disease and thalassemia) through a poorly understood mechanism. In addition, there appears to be another PXE-like syndrome with a similar phenotype but as a result of problems with another gene, gamma-glutamyl carboxylase. Mutations in ABCC6 can also cause generalized arterial calcification of infancy. In some cases of PXE, mutations in ABCC6 cannot be found, and other genes such as ENPP1 may be implicated

Pathophysiology
In PXE, there is mineralization (accumulation of calcium and other minerals) and fragmentation of the elastin-containing fibers in connective tissue, but primarily in the midlaminar layer of the dermis, Bruchs membrane and the midsized arteries. Recent studies have confirmed that PXE is a metabolic disease, and that its features arise because metabolites of vitamin K cannot reach peripheral tissues. Low levels of PPi cause mineralization in peripheral tissues. Diagnosis
The diagnostic criteria for PXE are the typical skin biopsy appearance and the presence of angioid streaks in the retina.
Estropipate, also known as piperazine estrone sulfate and sold under the brand names Harmogen, Improvera, Ogen, Ortho-Est, and Sulestrex among others, is an estrogen medication which is used mainly in menopausal hormone therapy in the treatment of menopausal symptoms. It is a salt of estrone sulfate and piperazine, and is transformed into estrone and estradiol in the body. It is taken by mouth. Medical uses
Estropipate is used to:
Alleviate symptoms of menopause as menopausal hormone therapy
Treat some types of infertility
Treat some conditions leading to underdevelopment of female sexual characteristics
Treat vaginal atrophy
Treat some types of breast cancer (particularly in men and postmenopausal women)
Treat prostate cancer
Prevent osteoporosis

Available forms
Estropipate is available in the form of 0.75, 1.5, 3, and 6 mg oral tablets. Pharmacology
Pharmacodynamics
Estropipate is a prodrug of estrone and estradiol. Hence, it is an estrogen, or an agonist of the estrogen receptors. Pharmacokinetics
Estropipate is hydrolyzed into estrone in the body. Estrone can then be transformed into estradiol by 17β-hydroxysteroid dehydrogenase. Chemistry
History
Estropipate was introduced for medical use by Abbott in 1968. It was approved by the FDA in the United States in 1991. Society and culture
Generic names
Estropipate is the generic name of the drug and its INN, USAN, and BAN. Brand names
Estropipate is or has been marketed under the brand names Genoral, Harmogen, Improvera, Ogen, Ortho-Est, and Sulestrex among others. Availability
Estropipate appears to remain available only in the United States. In the past, estropipate has also been marketed in Canada, the United Kingdom, Ireland, Switzerland, Australia, South Africa, Mexico, and Indonesia. == References ==