Understanding the cognitive impact of the contraceptive estrogen Ethinyl Estradiol: tonic and cyclic administration impairs memory, and performance correlates with basal forebrain cholinergic system integrity.

Ethinyl Estradiol (EE), a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives, and is found in at least 30 different contraceptive formulations currently prescribed to women as well as hormone therapies prescribed to menopausal women. Thus, EE is prescribed clinically to women at ages ranging from puberty to reproductive senescence. Here, in two separate studies, the cognitive effects of cyclic or tonic EE administration following ovariectomy (Ovx) were evaluated in young female rats. Study I assessed the cognitive effects of low and high doses of EE, delivered tonically via a subcutaneous osmotic pump. Study II evaluated the cognitive effects of low, medium, and high doses of EE administered via a daily subcutaneous injection, modeling the daily rise and fall of serum EE levels with oral regimens. Study II also investigated the impact of low, medium and high doses of EE on the basal forebrain cholinergic system. The low and medium doses utilized here correspond to the range of doses currently used in clinical formulations, and the high dose corresponds to doses prescribed to a generation of women between 1960 and 1970, when oral contraceptives first became available. We evaluate cognition using a battery of maze tasks tapping several domains of spatial learning and memory as well as basal forebrain cholinergic integrity using immunohistochemistry and unbiased stereology to estimate the number of choline acetyltransferase (ChAT)-producing cells in the medial septum and vertical/diagonal bands. At the highest dose, EE treatment impaired multiple domains of spatial memory relative to vehicle treatment, regardless of administration method. When given cyclically at the low and medium doses, EE did not impact working memory, but transiently impaired reference memory during the learning phase of testing. Of the doses and regimens tested here, only EE at the highest dose impaired several domains of memory; tonic delivery of low EE, a dose that corresponds to the most popular doses used in the clinic today, did not impact cognition on any measure. Both medium and high injection doses of EE reduced the number of ChAt-immunoreactive cells in the basal forebrain, and cell population estimates in the vertical/diagonal bands negatively correlated with working memory errors.

Antiovulatory and anti-implantation potential of the methanolic extract of seeds of Abrus precatorius in the rat.

OBJECTIVE: To investigate the effect of the methanolic extract of seeds of Abrus precatorius on the estrous cycle, ovulation, and implantation of fetuses in Sprague-Dawley rats. METHODS: Cyclic female rats were randomly classified into 4 groups (A through D). Treated rats in group A had daily vaginal smears for a total of 64 consecutive days while being fed A precatorius extract for the first 32 of those days. Treated rats in group B received a single oral dose of the extract on the day of proestrus and were killed the following morning so that shed ova could be counted. Treated rats in group C received A precatorius extract from postcoital day 1 to 10 and were killed on day 12 to assess for anti-implantation effect, whereas the treated dams in group D received the extract from the 6th to the 19th day of gestation. The control animals in all 4 groups received an equal volume of distilled water. RESULTS: The methanolic extract of A precatorius caused a reversible disruption in the estrous cycle of the regularly cyclic rats and completely blocked ovulation in all the treated rats. Despite successful mating of the female rats with male rats of proven fertility, uterine dissection on postcoital day 12 revealed neither implantation nor resorption sites in all the animals treated with A precatorius. The extract of A precatorius caused a decrease in mean body weight, mean crown-rump length, and mean tail length of fetuses of the treated rats. CONCLUSION: There is a need to continue the search for new antifertility agents that have minimal side effects and widespread acceptability in addition to being reversible, affordable, and accessible. In this study, methanolic extract of A precatorius seeds caused reversible alterations in the estrous cycle pattern and completely blocked ovulation in Sprague-Dawley rats. In addition, the extract demonstrated anti-implantation activity and the potential to affect gross fetal morphometry in rats.

Pharmacology and toxicology of ethinyl estradiol and norethindrone acetate in experimental animals.

For over 30 years various combinations of synthetic estrogens and progestins have been used in oral contraceptive formulations. Ethinyl estradiol (EE) and norethindrone acetate (NA) are common synthetic hormones used in oral contraceptives such as Loestrin, Brevicon, Ortho-Novum, Norlestrin, and Norinyl. In recent years these oral contraceptives have been considered for development in other therapeutic indications. Given the use of these agents for other clinical indications with different and larger target populations, an updated comprehensive review of the toxicology literature of estrogens and progestins is warranted. This review will summarize available data on the pharmacology and toxicology of estrogens and progestins with an emphasis on the specific synthetic hormones EE and NA. Ethinyl estradiol and norethindrone acetate alone or in combination, possess low acute and chronic toxicity. In some studies, EE and/or NA increased the incidence of specific tumors in susceptible strains of rodents and dogs, but not monkeys. These agents are not teratogenic when given in combination. Alone EE and NA have clastogenic properties. Overall, the animal data demonstrates that long-term exposure to EE and NA formulations pose very little health risks to humans.

Embryotoxicity and teratogenicity studies of an ayurvedic contraceptive--pippaliyadi vati.

An ayurvedic contraceptive--pippaliyadi vati, containing equal parts of powdered seeds or fruit berries of Embelia ribes, fruit of Piper longum and borax powder was fed orally to two groups of pregnant rats: 2.5 times to one and five times to the other; the recommended dose for humans. The foetuses of mothers fed with pippaliyadi had low birth weights and were smaller in length. The mothers gained less weight during gestation. Developmental defects of soft tissues and skeletons were analyzed. There were instances of herniation of the intestines into the umbilical cord in foetuses of mothers who were administered pippaliyadi. The control and the gum acacia groups did not show such herniation.

Ingestions considered nontoxic.

The authors have compiled a list of common household products and drugs that are frequently ingested by children and may be considered nontoxic unless taken deliberately or in large amounts. An understanding of the nontoxic ingestion should prevent overtreatment and decrease emergency room visits.

PIP: In 1980, the National Clearinghouse for Poison Control Centers (NCPCC) received 126,000 reports from Poison Control Centers, but the true incidence of ingestions was actually much higher. Only 1 in 50 ingestions may be reported, indicating that the majority of ingestions are innocuous. 70% of reported episodes occurred in children under 5 years of age. Nontoxic ingestions occur when a victim consumes a nonedible product that usually does not produce symptoms. No product is entirely safe and all can produce symptoms if a large enough concentration is consumed. Knowledge of nontoxic ingestions helps avoid overtreatment and its risks and serves as a warning of inadequate supervision or an improper and unsafe environment. The designation of nontoxic ingestion has 6 criteria: 1) absolute identification of the product 2) absolute assurance that only 1 product was ingested 3) no signal word (danger, poison, warning, caution) on the container 4) a good approximation of the amount ingested 5) assurance that the victim is free of symptoms and 6) the ability to call back at intervals to determine that no symptoms have developed. A good rule of thumb for the average drug that 5 times the therapeutic dose may be a toxic dose; opiate narcotics are the exception and require medical observation because of their narrow margin of safety. There are several points to consider in deciding wheter to decontaminate the gastrointestinal tract, including the toxicity of the ingested agent, the amount ingested, the elapsed time since ingestion, and the presence of symptoms. Emergency room referral is mandatory in case of exposure to highly toxic agents, of a dose sufficient to lead to anticipation of servere symptoms, of manifestations of toxic exposure such as alterations in vital signs already present, or of a history of intentional ingestion. A detailed discussion of frequently ingested nontoxic household items and related items that may be toxic includes writing and art materials, toiletries and laundry agents, deordorizers and disinfectants, tobacco and matches, medicinals, pesticides and insecticides, miscellaneous substances, petroleum distillate hydrocarbons, and plants. Hormonal contraceptives have been reported to produce almost no toxicity. A 1962-65 report from the NCPCC of 962 ingestions listed only 40 producing nausea nd vomiting even after consumption of 21 pills. An iron additive could make the ingestion toxic for iron.

Alteration of convulsive threshold and conditioned avoidance response in mice fed diets containing contraceptive steroids.

Female CD1 mice given the contraceptive steroids mestranol and norethynodrel (1:10) in the diet (0.0033%) for 4 months had a growth reduction of 20% when compared with mice fed a normal diet, and had lower convulsive thresholds when tested with the vitamin B6 antagonists 2,4-dimethyl-5-methyl-hydroxypyrimidine and thiosemicarbazide. In conditioned avoidance response (CAR) tests, mice fed the steroid-containing diets showed a decreased acquisition performance during all six sessions; however, mice fed the same diet supplemented with vitamin B6 (0.04%) performed as well during the last three sessions of the CAR tests as mice fed the normal diet.

A new non-steroidal drug for long-acting contraception.

A new contraceptive compound had been prepared with the common ingredients and it was applied in female rats. The efficacy and toxicity tests of this compound showed that this drug has along-acting contraceptive value not causing any side-effects.

An examination of some reputed antifertility plants.

Solvent extracts prepared from 80 plant species reputed to show antifertility effects on human beings or from species closely related to such plants, showed no significant antifertility activity when fed to rats.