Tiziana Ruggiero (238561) & Francesca Bar (239273)
The presence of sex differences in pain is confirmed but we don’t still understand the reasons
Gonadal hormones seem to be a prime candidate for accounting for the differences, but we have to note that gonadal hormones are secreted by the gonads but also by the adrenals.
Hormonal production by the gonads is stimulated by gonadotropin, while production by the adrenals follows hypothalamus–pituitary–adrenal axis activation.
Gonadal hormones were long considered to be involved only in sex-related reproductive functions, but they are now considered key actors in the modulation of cognitive processes, immune functions, microglial functions in neural repair, and other important activities.
As soon as the genetically determined sex develops physiologically (because the presence of androgen receptors [ARs] and estrogen receptors [ERs] are in the physiologic sites), the gonadal hormones (androgen and estrogen) model the female or male body.
- The organizational phase indicates the ability of these hormones to produce permanent changes in the CNS.
- In the adult, the effects induced by gonadal hormones are called activational and are transitory. This mean that they are not present only in certain phases, but opposite that all activational functions in our body (i.e. maintenance of sexual characteristics, bone and muscle metabolism and structure) can be quickly lost if the levels of gonadal hormones decrease.
Estradiol has been shown to induce both excitatory and inhibitory effects within the CNS nuclei.
In the CNS, one of the best-established hormonal interactions in the modulation of pain mechanisms is that between estradiol and the α-aminobutyric acid (GABA) system.
- Estradiol increases glutamic acid decarboxylase activity in neurons, to induce synaptosomal and hippocampal GABA release,
- to upregulate GABAA receptor number, to decrease the functional coupling of the μ-opioid and GABAB receptor to the inwardly rectifying potassium channel, and to increase GABAA -agonist binding affinity in the hippocampus.
- Changes in estrogen plasma levels are accompanied by changes in a variety of neurotransmitters, including serotonin (5-HT), acetylcholine, dopamine, and β-endorphin.
- estrogens upregulate 5-HT. The decrease of peripheral 5-HT accompanying low levels of estrogen can reduce selfinhibitory effects at the 5-HT receptor level. This effect seems to be associated with an increased occurrence of headache.
Estrogens may play a role in the activation of the molecular cascade involved in plastic adjustment of cellular functions. A close interaction, crosscoupling, and reciprocal regulation among estrogens and proteins involved in signal transduction mediated by neural growth factors or neurotransmitters has been demonstrated.
Estrogens were found to:
- modify nerve growth factor receptors in the dorsal root ganglia,
- induce c-Fos expression in the hippocampus,
- activate mitogen-activated protein kinase by a mechanism without ERs.
Mechanisms of action
Estrogens readily act on various CNS structures because their low molecular weight and lipophilic nature enable them to pass through the blood–brain barrier by passive diffusion.
But these steroids can also be produced in the CNS and their functions are often mediated by strong metabolites (i.e. DHT).
Since cellular answer to steroidal hormones depends on receptor levels, a mechanisms that modify receptor concentrations can control steroidal action.
Gonadal steroid actions are mediated by genomic and nongenomic mechanisms:
● In genomic actions, steroids bind a cytoplasmic or nuclear receptor and then the hormone receptor complex binds DNA and triggers RNA-dependent protein synthesis. The nuclear receptor includes a large family of transcription factors whose activity depends on the binding of a hormonal ligand. These processes produce a response for periods of several minutes to hours to days.
● In contrast, the nongenomic action is much more rapid. At present, a wide range of steroidal actions seems to be mediated by nongenomic cell membrane effects. These nontranscriptional actions are thought to be neuromodulatory in nature and critical for cell-to-cell communication:
1) a nonspecific effect on membrane fluidity caused by lipophilic properties of steroids,
2) binding to specific steroid membrane receptors,
3) binding and neuromodulation of neurotransmitter membrane receptors.
So is strongly suggested a modulatory role of gonadal hormones on brain areas involved in excitament and memory and in parameters shown to be affected by painful stimuli.
In women, gonadal hormones plasma levels change cyclically. A close relation between hormones and pain is clearly indicated by the pain syndromes related to the menstrual cycle phases.
For exemple, premenstrual migraine attacks, which occur just before menstruation when estrogen plasma levels are low, seem to be due to estrogen-mediated actions, such as a decrease the response of muscle cells to noradrenalin and a modification in the production of many vasoactive substances (i.e. prostacyclin and nitric oxide).
There have also been reports in fibromyalgia of symptom fluctuations throughout the menstrual cycle, with increased levels of pain, perceived stress, and depression reported during the luteal phase when levels of estrogen and progesterone are high.
Estrogens and SNC
Peripheral autonomic and sensory ganglion neurons and axons may be influenced by estrogens. Estrogens:
● reduce uterine myometrial noradrenaline and noradrenergic nerves,
● increase uterine cervical noradrenaline,
● influence the expression of neurotrophin receptors,
● increase the size of the genital receptive field,
● expand the size of the entire sensory-response region of the pudendal nerve.
This could be due to estrogens influencing sensory neurons of dorsal root ganglia.
Indeed, there are reports that ERs and ER mRNA are localized in a certain population of dorsal root ganglion neurons and that sensory neurons innervating the pelvic viscera express ERs.
Estrogen receptors are present in the lumbosacral spinal cord of both sexes, particularly in lamina II of the substantia gelatinosa and in the area surrounding the central canal.
Estrogen receptors in the dorsal horn of the lumbosacral region increase in density during proestrus when estrogens plasma levels are high. The demonstration of estrogen-sensitive neurons in the superficial dorsal horn lamina of the spinal cord suggests a mechanism by which changing levels of estrogens may regulate pain sensitivity, through its involvement in the transcriptional control of opioid synthesis and of opioid receptors.
Supraspinal central nervous system centers
It is now well understood that estrogens and androgens act supraspinally. Steroid-sensitive cells are found in the medial preoptic area, ventromedial and arcuate hypothalamic nuclei, lateral septum, bed nucleus of the stria terminalis, medial and cortical amygdaloid nuclei, and the mesencephalic central gray.
The synaptic organization in the ventromedial hypothalamic nucleus differs between the sexes and it is now generally accepted that estrogens affect the anatomy and physiology of the rodent hippocampus. Owing to these effects, similar hormone plasma levels could determine different functional activation of certain brain areas.
Gonadal hormones and stress
In addition to the physiologic changes of gonadal hormone levels occurring in women in the different periods of their life, gonadal hormones plasma levels can be modified by stressful stimuli. Chronic exposure to a stress can cause alterations of reproductive functions.
Stress such as psychological distress, exposure to environmental toxins, and strenuous exercise can result in ovarian dysfunction, affecting the hormonal qualities and even timing of menopause.
In fact, ovarian dysfunction presenting as secondary amenorrhea is more common in young women, affecting between 5% and 18% of women younger than 40 years. More then half of this premature ovarian failure is attributed to undetermined causes, which are often assumed to be environmental or psychogenic, giving rise to “functional hypothalamic amenorrhea.”
The influence of estrogen on migraine: a systematic review.2006