Gender Differences

Male to female ratio in autism - the role of steroids and calcium signalling

Autism affects more boys than girls, the overall male to female in autism being 4:1. One possible explanation for this difference in prevalence is the role of androgens. For example, it has been suggested that prenatal exposure to high levels of testosterone influences some autistic traits and makes fetuses more susceptible to developing autism [16624315]. Testosterone is a steroid hormone from the androgen group. It is derived from cholesterol, with largest amounts being produced by the Leydig cells in the testes in men, and some being produced by the adrenal glands, ovaries and in the placenta. Estrogens function as the primary female sex hormone and are present at significantly higher levels in women. Estradiol 17beta is one of the major naturally occurring estrogens.

A growing number of studies in recent years have shed light on the mechanisms behind the effect of testosterone on gender-related differences in cardiac preformance. It has been observed that testosterone induces an increase in calcium by increasing expression and activity of LTCC in coronary arteries, in particular the expression of Cav1.2 [9166901, 16243844, 15114516, 15242831]. Testosterone-induced increases in calcium levels appear to be G-protein linked and sensitive to Pertussis toxin treatment, and involve emptying of intracellular calcium stores downstream from LTCC activation [16339199]. Testosterone potentiation of calcium channels has also been observed in several other cells [8969193, 1883394].

On the other hand an increasing line of evidence indicates that estrogen acts as both cardioprotective as well as neuroprotective agent, primarily by inhibiting LTCC and rises in intercellular calcium levels [17082253]. Estradiol is thought to influence various brain functions by acting on receptors on the neuronal membrane surface. Many intracellular signaling pathways and modulatory proteins are affected by estradiol via this mechanism, including regulation of CREB, a stimulus-induced transcription factor that regulates various behaviors, including those related to addiction and chronic pain, as well as neuronal survival, proliferation, and differentiation (see Brain). One study has shown that estradiol attenuats CREB phosphorylation mediated by calcium influx through LTCC [15901789]. Administration of nifedipine, a calcium antagonist, mimicks the effects of estrogen on the peripheral nervous system [12732239]. Both nifedipine and estrogen protected neurons from amyloid-protein-induced toxicity through supression of calcium channel protein expression induced by this protein [15082219]. 17beta-estradiol was also able to attenuate glutamate-induced calcium overload in rat primary hippocampal neurons [15488487]. (see Hypoxia/Ischemia re protective effects of estrogen on brain arteries).

In addition, estrogen has been reported to have anti-oxidant properties - anti-oxidant effects of estrogen reduce intracellular calcium during metabolic inhibition and protect against damaging effect of calcium loading on mitochondria [12676548, 15723615] (see Mitochondria).

In terms of testosterone synthesis and secretion, calcium is an important modulator of Leydig cell steroidogenesis, which is mainly controlled by luteinizing hormone secreted from the anterior pituitary. Testosterone production in response to lutenising hormone is shown to be lower in the absence of extracellular calcium and in the presence of verapamil, a calcium channel blocking agent [9695359].

Testosterone formation in response to both lactate and to 4 beta-Phorbol-12-myristate-13-acetate (PMA) also appears to be dependent on extracellular calcium and could be blocked in vitro by the addition of the calcium channel blocking agents [2988910, 11500963].