Chemical synthesis of 7α-hydroxypregnenolone, a neuroactive steroid that stimulates locomotor activity.

7α-Hydroxypregnenolone is an endogenous neuroactive steroid that stimulates locomotor activity. A synthesis of 7α-hydroxypregnenolone from pregnenolone, which takes advantage of an orthogonal protecting group strategy, is described. In detail, the C7-position was oxidized with CrO3 and 3,5-dimethylpyrazole to yield a 7-keto steroid intermediate. The resulting 7-ketone was stereoselectively reduced to the 7α-hydroxy group with lithium tri-sec-butylborohydride. In contrast, reduction of the same 7-ketone intermediate with NaBH4 resulted in primarily the 7ß-hydroxy epimer. Furthermore, in an alternative route to the target compound, the 7α-hydroxy group was successfully incorporated by direct C-H allylic benzoyloxylation of pregnenolone-3-acetate with CuBr and tert-butyl peroxybenzoate followed by saponification. The disclosed syntheses to 7-oxygenated steroids are amenable to potentially obtain other biologically active sterols and steroids.

Nongenomic actions of neurosteroid pregnenolone and its metabolites.

Steroids have been widely used in the clinical setting. They bind and activate nuclear receptors to regulate gene expression. In addition to activating genomic transcription, steroids also exert nongenomic actions. The current article focuses on the nongenomic actions of neurosteroids, including pregnenolone (P5), 7α-hydroxypregnenolone, pregnenolone sulfate and allopregnanolone. Pregnenolone and its derivatives promote neuronal activity by enhancing learning and memory, relieving depression, enhancing locomotor activity, and promoting neuronal cell survival. They exert these effects by activating various target proteins located in the cytoplasm or cell membrane. Pregnenolone and its metabolites bind to receptors such as microtubule-associated proteins and neurotransmitter receptors to elicit a series of reactions including stabilization of microtubules, increase of ion flux into cells, and dopamine release. The wide actions of neurosteroids indicate that pregnenolone derivatives have great potential in future treatment of neurological diseases.

Optimizing the use of 17P in pregnant managed Medicaid members.

OBJECTIVE: To evaluate the effect of 17 alpha-hydroxyprogesterone caproate (17P) on reducing the rate of neonatal intensive care unit (NICU) admissions and premature births in a managed Medicaid population that has a history of preterm delivery. Specifically, to measure the effect of initiating 17P treatment during the recommended time frame of 16-21 weeks gestation versus after 21 weeks gestation. DESIGN: A 2004-2007 observational, causal comparative study reviewed birth outcomes in 104 pregnant women with a confirmed history of preterm delivery. Women whose 17P treatment was initiated during the recommended time frame of 16-21 weeks gestation were compared to those whose treatment was initiated after 21 weeks gestation. METHODOLOGY: Intervention included offering 17P as a benefit to pregnant women who had a history of preterm delivery and who were deemed to be appropriate candidates for this treatment by their physician. RESULTS: No significant changes in birth outcomes were noted when comparing those members whose treatment was initiated during the recommended time frame of 16-21 weeks versus those whose treatment began after 21 weeks gestation. Members who received therapy of at least five injections of 17P, as opposed to those receiving fewer than five injections, experienced a statistically significant reduction in NICU admissions and in preterm birth at fewer than 37 weeks and at fewer than 32 weeks. CONCLUSION: The number of injections and not the time frame, which had been indicated by previous research, the initiation of 17P therapy is the factor in reducing preterm birth and decreasing NICU admissions for pregnant women with a history of preterm birth in a managed Medicaid population.

Role of progestogens for the prevention of premature birth.

Premature birth represents a major cause of perinatal morbidity and mortality. The short- and long-term sequelae of prematurity have serious consequences for newborn survival and health in later life. In addition, prematurity is a major problem with regard to health expenditure. Despite major progress in obstetrics, perinatology and neonatology, the percentage of premature birth persists and there is even a tendency towards a slight increase. Therefore, besides screening programmes for the detection of vaginal infections, additional therapeutic opportunities must be sought. According to previously published data, vaginal progesterone and intramuscular 17alpha-hydroxyprogesterone caproate should be considered possible treatment options for the prevention of preterm delivery.

[Prevention of preterm delivery with gestagens]. / Prävention der Frühgeburtlichkeit durch Gestagene.

Preterm delivery with its short-term and long-term sequealae constitutes a serious problem in terms of morbidity, disability and mortality of the newborn and cost to the society. The incidence of premature deliveries persists and according to the latest national and international reports a tendency for an increase has been observed. Therefore, besides screening programmes for the detection of vaginal infections one has to look for additional therapeutic concepts. According to previous data and recent publications, progesterone vaginally and 17alpha-hydroxyprogesterone caproate intramuscularely should be considered as possible treatment options for the prevention of preterm delivery in high-risk women, with therapy starting in the second trimester.

Serum concentrations of delta 5-3 beta-hydroxysteroids in type 2 diabetes mellitus.

We examined the serum concentrations of delta(5)-3beta-hydroxysteroids, pregnenolone (Preg), 17-hydroxypregnenolone (17-OH-Preg), dehydroepiandrosterone (DHEA), androstenediol (ADIOL) and their sulfates in 30 well controlled (Group I: HbA1c<7.0%) and 15 poorly controlled (Group II: HbA1c>7.1%) type 2 diabetic patients, and 30 normal controls. These patients were treated with diet therapy or anti-diabetic agent. The distribution of gender and age of the subjects were matched between the groups. The serum levels of sulfo-conjugated and unconjugated steroids described above were measured by GC-MS and enzyme immunoassay (EIA), respectively. The serum levels of the entire sulfo-conjugated steroid measured in this study were significantly lower in Groups I and II than in controls. On the other hand, Preg levels in both Groups I and II were significantly higher than those in controls, whereas the serum levels of the downstream unconjugated steroids were not different from controls. To investigate the effect of sulfonylurea (SU) on the serum levels of steroids, the serum concentrations of steroids between the patients who were treated with diet therapy and SU agent were compared in Group I. No significant differences were observed between both groups. These results suggest that (1) since increased Preg levels did not cause any changes in the downstream delta(5)-3beta-hydroxysteroid levels, the metabolic pathway of delta(4)-3-ketosteroids may be accelerated in type 2 diabetes; (2) serum steroid levels were not affected by SU treatment; (3) sulfo-conjugated steroid catabolism was altered in type 2 diabetes; (4) the decreased sulfo-conjugated steroids especially ADIOLS may contribute to the alteration of sex steroid levels and onset or exacerbate infectious diseases in diabetes.

Dehydroepiandrosterone reduces progressive dermal ischemia caused by thermal injury.

Progressive ischemia and necrosis of the skin following thermal injury are reduced by postburn administration of the steroid hormone dehydroepiandrosterone (DHEA). Thermally injured animals were provided with a subcutaneous injection of DHEA, or a related species of steroid hormone, at various times after burning. During the 96 hr following administration of the scald burn, tissue necrosis was closely monitored. Subcutaneous administration of DHEA at approximately 1 mg/kg/day achieved optimal protection against the development of progressive dermal ischemia. DHEA, 17 alpha-hydroxy-pregnenelone, 16 alpha-bromo-DHEA, and androstenediol each demonstrated, a similar level of protection. Other forms of steroids, including DHEA sulfate, androstenedione, 17 beta-estradiol, or dihydrotestosterone, exhibited no protective effect under the conditions tested. Additionally, intervention therapy with DHEA could be initiated up to 4 hr, but not 6 hr, after burn without a marked reduction in therapeutic benefit. Examination of the microvasculature of thermally injured dorsal skin suggested that postburn intervention with DHEA, either directly or indirectly, maintained a normal architecture in most of the dermal capillaries and venules within burn-exposed tissue. These findings suggest that systemic intervention therapy of burn patients with DHEA or a similar acting steroid hormone may be useful in preventing the progressive tissue destruction caused by progressive ischemia.