Among all CDSs, estradiol-CDS is in the most advanced investigation stage, and it is currently undergoing phase I and II clinical trials. Estrogens are lipophilic steroids that are not impeded in their entry to the central nervous system (CNS). They can readily penetrate the BBB and achieve high central levels after peripheral administration, but, unfortunately, estrogens are poorly retained within the brain. Therefore, to maintain therapeutically significant concentrations, frequent doses have to be administered. Constant peripheral exposure to estrogens has been related, however, to a number of pathological conditions including cancer, hypertension, and altered metabolism [106-109]. Because the CNS is the target site for many estrogenic actions, brain-targeted delivery may provide safer and more effective agents. Estrogen CDSs could be useful in reducing the secretion of luteinizing hormone-releasing hormone (LHRH) and, hence, in reducing the secretion of luteinizing hormone (LH) and gonadal steroids. As such, they could be used to achieve contraception and to reduce the growth of peripheral steroid-dependent tumors, such as those of the breast, uterus, and prostate, and to treat endometriosis. They also could be useful in stimulating male and female sexual behavior, and in the treatment of menopausal vasomotor symptoms (''hot flushes'') . Other potential uses are in neuroprotection, in the reduction of body weight, or in the treatment of depression and various types of dementia, including Alzheimer's disease [108, 111, 112]. Alzheimer's disease, which still has no specific cure, results in progressively worsening symptoms that range from memory loss to declining cognitive ability. It affects an estimated 10% of the population older than 65 years of age and almost 50% of those older than 85 years of age .
Estradiol (E2) (7, Figure 5) is the most potent natural steroid. It contains two hydroxy functions: one in the phenolic 3 position and one in the 17 position. With these synthetic handles, three possible CDSs can be designed attaching the targetor at the 17-, at the 3-, or at both positions. Attachment at either position, but especially at the 17 position, should greatly decrease the pharmacological activity of E2, because these esters are known not to interact with estrogen receptors .
Since its first synthesis in 1986 , E2-CDS (5) has been investigated in several models [116-130]. In vitro studies with rat organ homogenates as the test matrix indicated half-lives of 156.6 min, 29.9 min, and 29.2 min (T at the 17 position) in plasma, liver, and brain homogenates, respectively . Thus, E2-CDS is converted to the corresponding quaternary form (T+-E2) (6) faster in the tissue homogenates than in plasma. This is consistent with the hypothesis of a membrane-bound enzyme, such as the members of the NADH transhydrogenase family, acting as oxidative catalyst. These studies also indicated a very slow production of E2 from T+-E2, suggesting a possible slow and sustained release of estradiol from brain deposits of T+-E2.
To detect doses of E2-CDS (5), T+-E2 (6), and E2 (7) of physiological significance, a selective and sensitive method was needed. This problem was solved using a precolumn-enriching high-performance liquid chromatography system  that allowed accurate detection in plasma samples and organ homogenates with limits of 10, 20, and 50 ng/mL or ng/g for T+-E2, E2-CDS, and E2, respectively. This study proved that in rats, E2 released from the T+-E2 intermediate formed after IV E2-CDS administration has an elimination half-life of more than 200 h (Figure 7) and brain E2-levels are elevated four to five times longer after administration than after simple estradiol treatment . Proving effective targeting, another study also found that steroid levels between 1 and 16 days after E2-CDS treatment were more than 12-fold greater in brain samples than in plasma samples . Studies in orchidectomized rats proved that a single IV injection of E2-CDS (3 mg/kg) suppressed LH secretion by 88%, 86%, and 66% relative to dimethyl sulfoxide (DMSO) controls at 12, 18, and 24 days, respectively, and that E2 levels were not elevated relative to the DMSO control at any sampling time . A single IV administration of doses as low as 0.5 mg/kg to ovariecto-mized rats induced prolonged (3-6 weeks) pharmacological effects as measured
by LH suppression [116, 118, 125], reduced rate of weight gain [119, 123-125], or, in castrated male rats, re-establishment of copulatory behavior . A large number of other encouraging results have been obtained in various animal models and phase I/II clinical trials; most of them have been reviewed previously [74, 126, 128]. Clinical evaluations suggest a potent central effect with only marginal elevations in systemic estrogen levels; therefore, E2-CDS may become a useful and safe therapy for menopausal symptoms or for estrogen-dependent cognitive effects.
Recently, E2-CDS also was shown to provide encouraging neuroprotective effects. In ovariectomized rats, pretreatment with E2-CDS decreased the mortality caused by middle cerebral artery (MCA) occlusion from 65-16% . Even when administered 40 or 90 min after MCA occlusion, E2-CDS reduced the area of ischemia by 45-90% or 31%, respectively. Another recent study provided evidence that treatment with E2-CDS can protect cholinergic neurons in the medial septum from lesion-induced degeneration .
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Are Menopause Symptoms Playing Havoc With Your Health and Relationships? Are you tired of the mood swings, dryness, hair loss and wrinkles that come with the change of life? Do you want to do something about it but are wary of taking the estrogen or antidepressants usually prescribed for menopause symptoms?