Chronic Inhibition of Hypothalamic-Pituitary-Ovarian Axis and Body Weight Gain by Brain-Directed Delivery of Estradiol-17β in Female Rats

Abstract

The effect of preferential delivery of estradiol (E2) into the brain on both the hypothalamic-pituitary-ovarian axis and weight gain was studied in female rats. When E₂ was coupled to a lipoidal dihydropyridine-pyridinium carrier, the resulting carrier E₂ complex (CE), upon a single intravenous administration to cycling female rats, caused a dose-dependent inhibition of ovulation which lasted 3 times longer than with uncoupled E₂. The dose of CE that delayed ovulation for 4 days was one twentieth the amount of E₂ needed to produce the same effect. Studies in ovariectomized (OVEX) rats indicated that the prolonged ovulation-blocking action of CE appeared to be related to a sustained storage and release of E₂ in the brain, which in turn suppressed the release of hypothalamic luteinizing hormone-releasing hormone (LHRH) and pituitary luteinizing hormone (LH). Upon single intravenous administration in pubertal female rats, CE caused a dose-dependent reduction of body weight gain for a minimum period of 28 days. The inhibitory action of CE on body weight gain was more potent and longer lasting than that of E₂ in pubertal rats. When administered in OVEX rats, CE produced a loss of body weight that lasted significantly longer than that produced by uncoupled E₂ in these rats. These results suggest that the biological action of E₂ can be potentiated by this novel chemical delivery system.

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“…In female rats, an increased number of apoptotic corpora lutea at ‡0.05 mg ethinylestradiol/kg in study B and an increased number of early stage follicles in both studies at 0.2 mg/kg was observed and might reflect inhibition of the hypothalamic-pituitary-ovarian axis (Sarkar et al 1989) and/or a direct estrogenic effect. Classical direct estrogenic effects on the uterus were observed.…”

Retrometabolism‐Based Drug Design and Targeting

“…injection of E 2 -CDS (3 mg/kg) suppressed LH secretion by 88%, 86%, and 66% relative to DMSO controls at 12, 18, and 24 days, respectively, and that E 2 levels were not elevated relative to the DMSO control at any sampling time [465]. A single i. v. administration of doses as low as 0.5 mg/kg to ovariectomized rats induced prolonged (3-6 weeks) pharmacological effects as measured by LH suppression [463,465,473], reduced rate of weight gain [466,[471][472][473], or, in castrated male rats, reestablishment of copulatory behavior [464]. A large number of other very encouraging results have been obtained in various animal models; most of them have been reviewed previously [33,340,475,476,478,484].…”

“…Since its first synthesis in 1986 [462], E 2 -CDS (194) has been investigated in several models [463][464][465][466][467][468][469][470][471][472][473][475][476][477][478][479][480][481][482]484]. In vitro studies with rat organ homogenates as the test matrix indicated half-lives of 156.6, 29.9, and 29.2 min for E 2 -CDS (T at the 17-position) in plasma, liver, and brain homogenates, respectively [462].…”

“…51) [469]. As a further proof of effective targeting, another study also found that steroid levels between 1 and 16 days after E 2 -CDS treatment were more than 12-fold higher in brain samples than in plasma samples [473]. Studies in orchidectomized rats proved that a single i.v.…”

A review and primer of molecular genetic studies of anorexia nervosa

“…Estrogens might be one set of additional biologic and genetic risk factors that contribute to AN. The anorectic effects of estrogens have been noted for decades 46,47 and the estrogen receptor b (ERb) gene has shown associations with both AN and BN. 48,49 This gene is also located on chromosome 14, which was found to be in significant linkage with BN.…”