The effects of ethinylestradiol and progestins ("the pill") on cognitive function in pre-menopausal women

Oral contraceptives (OCs), often referred to as "the pill", are the most commonly employed form of reversible contraception. OCs are comprised of combined synthetic estrogen and progestin, which work to suppress ovulation and subsequently protect against pregnancy. To date, almost 200 million women have taken various formulations of OC, making it one of the most widely consumed classes of medication in the world. While a substantial body of literature has been dedicated to understanding the physical effects of OCs, much less is known about the long term consequences of OC use on brain anatomy and the associated cognitive effects. Accumulating evidence suggests that sex hormones may significantly affect human cognition. This phenomenon has been commonly studied in older populations, such as in post-menopausal women, while research in healthy, pre-menopausal women remains limited. The current review focused on the effects of OCs on human cognition, with the majority of studies comparing pre-menopausal OC users to naturally cycling women. Human neuroimaging data and animal studies are also described herein. Taken together, the published findings on OC use and human cognition are varied. Of those that do report positive results, OC users appear to have improved verbal memory, associative learning and spatial attention. We recommend future research to employ blinding procedures and randomised designs. Further, more detailed information pertaining to the specific generation and phasic type of OCs, as well as menstrual cycle phase of the OC non-users should be considered to help unmask the potential impact of OC use on human cognition.

Visualization of HIV-1 interactions with penile and foreskin epithelia: clues for female-to-male HIV transmission

To gain insight into female-to-male HIV sexual transmission and how male circumcision protects against this mode of transmission, we visualized HIV-1 interactions with foreskin and penile tissues in ex vivo tissue culture and in vivo rhesus macaque models utilizing epifluorescent microscopy. 12 foreskin and 14 cadaveric penile specimens were cultured with R5-tropic photoactivatable (PA)-GFP HIV-1 for 4 or 24 hours. Tissue cryosections were immunofluorescently imaged for epithelial and immune cell markers. Images were analyzed for total virions, proportion of penetrators, depth of virion penetration, as well as immune cell counts and depths in the tissue. We visualized individual PA virions breaching penile epithelial surfaces in the explant and macaque model. Using kernel density estimated probabilities of localizing a virion or immune cell at certain tissue depths revealed that interactions between virions and cells were more likely to occur in the inner foreskin or glans penis (from local or cadaveric donors, respectively). Using statistical models to account for repeated measures and zero-inflated datasets, we found no difference in total virions visualized at 4 hours between inner and outer foreskins from local donors. At 24 hours, there were more virions in inner as compared to outer foreskin (0.0495 +/- 0.0154 and 0.0171 +/- 0.0038 virions/image, p = 0.001). In the cadaveric specimens, we observed more virions in inner foreskin (0.0507 +/- 0.0079 virions/image) than glans tissue (0.0167 +/- 0.0033 virions/image, p<0.001), but a greater proportion was seen penetrating uncircumcised glans tissue (0.0458 +/- 0.0188 vs. 0.0151 +/- 0.0100 virions/image, p = 0.099) and to significantly greater mean depths (29.162 +/- 3.908 vs. 12.466 +/- 2.985 μm). Our in vivo macaque model confirmed that virions can breach penile squamous epithelia in a living model. In summary, these results suggest that the inner foreskin and glans epithelia may be important sites for HIV transmission in uncircumcised men.

Defining the interaction of HIV-1 with the mucosal barriers of the female reproductive tract

Worldwide, HIV-1 infects millions of people annually, the majority of whom are women. To establish infection in the female reproductive tract (FRT), HIV-1 in male ejaculate must overcome numerous innate and adaptive immune factors, traverse the genital epithelium, and establish infection in underlying CD4(+) target cells. How the virus achieves this remains poorly defined. By utilizing a new technique, we define how HIV-1 interacts with different tissues of the FRT using human cervical explants and in vivo exposure in the rhesus macaque vaginal transmission model. Despite previous claims of the squamous epithelium being an efficient barrier to virus entry, we reveal that HIV-1 can penetrate both intact columnar and squamous epithelial barriers to depths where the virus can encounter potential target cells. In the squamous epithelium, we identify virus entry occurring through diffusive percolation, penetrating areas where cell junctions are absent. In the columnar epithelium, we illustrate that virus does not transverse barriers as well as previously thought due to mucus impediment. We also show a statistically significant correlation between the viral load of inocula and the ability of HIV-1 to pervade the squamous barrier. Overall, our results suggest a diffusive percolation mechanism for the initial events of HIV-1 entry. With these data, we also mathematically extrapolate the number of HIV-1 particles that penetrate the mucosa per coital act, providing a biological description of the mechanism for HIV-1 transmission during the acute and chronic stages of infection.

Inhibition of the secretion of LH in ovariectomised pigs by sustained but not repeated acute elevation of cortisol in the absence but not the presence of oestradiol

Prolonged stress is known to impair reproduction. It has been proposed that reproduction will also be impaired when a severe acute stress occurs during a period of elevated plasma concentrations of oestradiol, such as during the follicular phase of the oestrous cycle. In this experiment, we hypothesised that repeated acute and sustained elevation of cortisol would suppress the secretion of LH in ovariectomised pigs and that these effects would be enhanced in the presence of oestradiol negative feedback. Cortisol (or vehicle) was administered 12 hourly to ovariectomised pigs (n=6/treatment) for 8 days in the absence of oestradiol treatment and for a further 8 days during treatment with oestradiol. Vehicle was administered to 'control' pigs, 10 or 20 mg cortisol was administered i.v. to pigs to produce 'repeated acute' elevation of cortisol and 250 mg cortisol was administered i.m. to pigs to give a 'sustained' elevation of cortisol. Both before and during treatment with oestradiol, plasma concentrations of LH were monitored on the day before treatment, on the 4th and 8th days of treatment and following an i.v. injection of GnRH at the end of the 8th day of treatment. The repeated acute elevation of cortisol did not impair any parameters of LH secretion (i.e. mean plasma concentrations of LH, pulse amplitude or frequency, pre-LH pulse nadir or the LH response to GnRH) in the absence or in the presence of oestradiol. In contrast, when the elevation of cortisol was sustained, the mean plasma concentrations of LH and the pre-LH pulse nadir were significantly (P<0.05) lower on the 8th day of treatment than on the day before treatment and on the 4th day of treatment. Nevertheless, no other parameters of LH secretion were affected and these effects only occurred in the absence (not in the presence) of oestradiol. In conclusion, cortisol needed to be elevated for more than 4 days to impair the secretion of LH, and oestradiol did not enhance the impact of cortisol on LH secretion in ovariectomised pigs.

Effects of stress on reproduction in non-rodent mammals : the role of glucocorticoids and sex differences

The means by which stress influences reproduction is not clearly understood, but may involve a number of endocrine, paracrine and neural systems. Stress impacts on the reproductive axis at the hypothalamus (to affect GnRH secretion) and the pituitary gland (to affect gonadotrophin secretion), with direct effects on the gonads being of less importance. Different stressors have different effects and there are differences in response to short- and long-term stress. Many short-term stresses fail to affect reproduction and there are reports of stimulatory effects of some 'stressors'. There are species differences in the way that specific stressors affect reproduction. Sex differences in the effects of a particular stressor have been delineated and these may relate to effects of stress at different levels of the hypothalamo-pituitary axis. The significance of stress-induced secretion of cortisol varies with species. In some instances, there appears to be little impact of short-term increases in cortisol concentrations and protracted increases in plasma concentration seem to be required before any deleterious effect on reproduction is apparent. Issues of sex, sex steroid status, type of stressor and duration of stress need to be considered to improve understanding of this issue.

Stress and reproduction: central mechanisms and sex differences in non-rodent species

Despite extensive research, the mechanisms by which stress affects reproduction are unknown. Activation of stress systems could potentially influence reproduction at any level of the hypothalamo-pituitary gonadal axis. Nonetheless, the predominant impact is on the secretion of gonadotrophin releasing hormone (GnRH) from the brain and the secretion of the gonadotrophins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), from the gonadotrophs of the anterior pituitary gland. When stress is prolonged, it is likely that secretion of the gonadotrophins will be suppressed but the effects of acute stress or repeated acute stress are not clear. Different stressors activate different pathways for varying durations, and the actions of stress vary with sex and are influenced by the predominance of particular sex steroids in the circulation. The mechanisms by which stress influences reproduction are likely to involve complex interactions between a number of central and peripheral pathways and may be different in males and females. To understand these mechanisms, it is important to determine the stress pathways that are activated by particular stressors and to establish how these pathways affect the secretion and actions of GnRH. Furthermore, there is a need to know how stress influences the feedback actions of gonadal steroids and inhibin.