Being lipids, steroid hormones enter the cell by simple diffusion across the plasma membrane. Thyroid hormones enter the cell by facilitated diffusion. The receptors exist either in the cytoplasm or nucleus, which is where they meet the hormone. When hormone binds to receptor, a characteristic series of events occurs:. As might be expected, there are a number of variations on the themes described above, depending on the specific receptor in question. For example, in the absense of hormone, some intracellular receptors do bind their hormone response elements loosely and silence transcription, but, when complexed to hormone, become activated and strongly stimulate transcription.
Some receptors bind DNA not with another of their kind, but with different intracellular receptor. As a specific example, consider glucocorticoids , a type of steroid hormone that probably affects the physiology of all cells in the body. The image to the right depicts a pair of glucocorticoid receptors blue and green on the top bound to their DNA hormone response element bottom. The two steroid hormones are not visible in this depiction.
Menarche usually indicates that the first ovulation has occurred Once the reproductive system fully matures, women between 12 and 50 years of age normally exhibit regular ovulations characterized by to day cycles with fluctuating plasma estradiol and progesterone values according to the different phases of the cycle Figure 1A Box 1. Figure 1. Diagram of fluctuating plasma estradiol green and progesterone yellow values according to the different phases of the ovarian continuum upper: A—F , and three different forms of exogenous hormone administration bottom: G—I.
Box 1. Main hormonal steps during a normal ovulatory cycle Follicle stimulating hormone FSH level increase leads to recruitment and development of ovarian follicles. Estradiol, together with inhibin, exerts a negative feedback upon the hypothalamic-pituitary-gonadal HPG axis decreasing FSH levels. Estradiol also has a negative feedback effect on the kisspeptinergic neurons Estradiol levels, produced by the dominant follicle, rise to peak levels and, together with a small rise in progesterone, exert a positive feedback on the kisspeptinergic neurons, hypothalamus, and hypophysis.
Progesterone rises due to follicular luteinization and the corpus luteum is formed. The corpus luteum secretes progesterone and estrogens, which further inhibits follicular development. Estradiol and progesterone concentrations drop, eliminating the negative feedback exerted upon the HPG axis. The functional capacity of the ovary diminishes with age. Approximately 4 years before their final menstrual period menopause , women enter the perimenopausal period 31 characterized by symptoms such as headaches, sleep disturbances, mood fluctuations, anxiety, depressive symptoms, impairment in cognitive function, hot flashes and, later on, vaginal dryness and bone fractures, among others 32 , During this period, due to gonadotropin stimulation, increased estrogen levels are produced by the ovaries, which cause endometrial growth that can be associated with heavy bleeding and irregular cycles Hormonal levels will reach a state of little or no fluctuation approximately 2 years after menopause, when estradiol and progesterone values remain low Figure 1A , while FSH levels remain high A decrease in steroid hormones has been associated with cognitive impairments, reflected in a higher incidence of neurodegenerative diseases such as Alzheimer's disease It is important to consider the effects that the aging process has on the reproductive axis, particularly at the CNS level With age, the hypothalamic GnRH neurons, that contribute to regulate the cyclicity of the menstrual cycle, are affected in a functional and morphological manner For this reason, it is not possible to completely isolate the aging phenomena of the endocrine system from the aging processes that occur in the nervous system.
According to the concept of the ovarian continuum 1 , cycles can be classified as follows:. Cycles with no ovarian activity, in which estradiol and progesterone plasma levels are low. This type of ovarian activity will be present in childhood and menopause. It can also be found in cases such as anorexia and hypogonadotropic hypogonadism Figure 1A.
Anovulatory cycles with fluctuating estrogen levels. Estrogen levels will start to rise, but will not be adequate to induce a luteinizing hormone LH rise and ovulation. This type of ovarian activity will be found during pubertal development and, for example, in women who are partially breastfeeding Figure 1B.
This pattern of ovarian activity can be found in women with Polycystic Ovarian Syndrome, usually associated with the presence of increased adiposity because adipocytes can produce estradiol in considerable amounts Figure 1C. This type of ovarian activity can be found during the perimenopausal period and in cases of hyperprolactinemia Figure 1D.
As the previous type of activity, this pattern can also be found after breastfeeding during the period of returning fertility, the menopausal transition, and in women presenting hypothyroidism and hyperprolactinemia Figure 1E. This is the type of ovarian activity present when an adequate hormonal balance between estradiol and progesterone is found Figure 1F When the hormonal balance between estrogen and progesterone is disrupted, women are at greater risk of experiencing neurocognitive dysfunctions 5.
For this reason, whenever a woman is being treated for a mental health condition, her pattern of ovarian activity should be taken into consideration. Some of the mechanisms that may help to elucidate why this association occurs are described below.
The activation of the EREs results in gene transcription at the nuclear and mitochondrial levels. Through these receptors, estrogen triggers the activation of different signaling cascades such as phosphatidylinositolkinase PI3K , phospholipase C PLC , and mitogen-activated protein kinases MAPK , second messengers, ion influx, and efflux. Finally, genomic transcription can also be induced by the non-classical pathway The activation of both pathways via estrogenic action will exert a neuroprotective effect in the CNS through different mechanisms:.
Estrogen action also enhances the transcription of anti-apoptotic genes such as BCL2 B-cell lymphoma 2 Among its functions, BCL2 protects cells from excess of intracellular calcium by promoting its mitochondrial uptake and preventing the activation of different calcium-dependent enzymes that would damage cell structures Yet another mechanism by which estrogen enhances neuronal survival occurs through its activity in mitochondrial DNA, where it enhances the expression of enzymes that reduce free radicals, diminishing oxidative damage, and its consequential apoptotic process These mechanisms are possible due to the increase in the number of glucose transporters, glucose uptake, and the activity of glycolytic enzymes in aerobic glycolysis Estrogen also increases the transcription of proteins and metabolic enzymes i.
In this way, this gene not only has a neuroprotective effect, as explained above, but also contributes to regulate bioenergetic systems 43 , It has been shown that this action is due to a rise in MAPK which in turn increases the neurotrophic factor BDNF, which protects neurons from degeneration 14 , 49 , Progesterone, and some of its neuroactive metabolites, such as allopregnanolone and dihydroprogesterone DHP , also act through the non-classical pathway.
Both the classical and non-classical pathways of progesterone have neuroprotective effects in the CNS causing: i a rise in anti-apoptotic mechanisms and cell survival, ii regulation of the bioenergetic systems 47 , and iii induction of neural cell proliferation more consistently than estrogen It must be emphasized that, although, estrogen and progesterone are potent regulators of cell survival, bioenergetic systems, and neurogenesis; the combination of estrogen and progesterone is not synergistic and, when administered in combination, at the same time, leads to a lower response compared to either hormone administered alone or in sequence 47 , Another neuroprotective role of progesterone is its regulatory effect upon glial cells, where myelination has special relevance In the peripheral nervous system myelin is synthesized by Schwann cells, while oligodendrocytes accomplish this in the CNS In the CNS, one oligodendrocyte can extend up to 40 processes onto multiple adjacent axons, thus, each oligodendrocyte influences the electrical activity of a large number of axons Oligodendrocytes can proliferate from oligodendrocyte progenitor cells OPC , which migrate toward unmyelinated axons, where they mature and form processes able to form the myelin sheath Progesterone plays an important role in the stimulation of these steps 58 by promoting intracellular signaling, proliferation of oligodendrocyte progenitors, and transcription of key components in the synthesis pathways of myelin i.
Oligodendrocytes and their precursors produce high amounts of progesterone and metabolize progesterone from the bloodstream, or other sources, into DHP and allopregnanolone. It has been shown that, like progesterone, DHP also plays a role in the regulation of oligodendrocyte function and myelination Therefore, progesterone and its metabolites have an important role in promoting cellular maturation and oligodendrocyte function in the CNS Figure 2.
Figure 2. Schematic view of A estradiol and B progesterone signaling in neural cells through both classical and non-classical pathways. In the classical signaling pathway right the steroid hormone binds to its receptor located in the cytoplasm; the activated receptor dimerizes and makes its way into the nucleus where it interacts with responsive elements to activate or inhibit gene transcription.
Also steroid hormones can bind to mitochondrial receptors that regulate mitochondrial DNA transcription. In the non-classical pathway left steroid hormones act through membrane receptors, including the classical receptors, GPCR receptors, ionotropic receptors, tyrosine kinase receptors, and other neurotransmitter receptors. This non-classical pathway initiates cytosolic signaling cascades, modulating the activation of various proteins and of second messenger systems.
Additionally, progesterone and its metabolites promote myelination and remyelination at the oligodendrocyte level in the CNS and that of Schwann cells in the PNS. Through the classical pathway, via PR, progesterone and DHP bind to myelin gene promoters P0 and P1, which express myelin sheath specific proteins [i.
Through these mechanisms, progesterone and its metabolites modulate the myelination and remyelination processes in the PNS. It is important to mention that some of these actions could explain the fundamental role of progestogens in myelin repair under neurodegenerative conditions Neurosteroids participate in the regulation and modulation of neurotransmitter systems and neuronal excitability.
We will briefly describe the main role of four main neurotransmitters: glutamate, gamma-Aminobutyric acid GABA , serotonin 5-HT , and dopamine; as well as some mechanisms through which estradiol, progesterone, and their metabolites act at the synaptic level Figure 3. Glutamate is the main excitatory neurotransmitter in the brain and glutamatergic synapses can be found from the prefrontal cortex to brainstem areas, striatum, nucleus accumbens, thalamus, hypothalamus, and hippocampus It is involved in cognitive processes such as memory and learning GABA is the most abundant inhibitory neurotransmitter in the brain GABAergic synapses are found in the striatum, substantia nigra, brainstem, thalamus, hippocampus, basal ganglia, and cerebellum.
Since it has a fundamental role in balancing brain cell activity, alterations in these pathways can cause anxiety. Inversely, the potentiation of its synapses causes anxiolysis, as in the case of benzodiazepines. Serotonin 5-HT has an important role in the limbic system Serotonergic pathways extend from the raphe nuclei to all areas of the forebrain including the frontal cortex, striatum, thalamus, amygdala, hypothalamus, and hippocampus They are important contributors to a sense of well-being.
Serotonergic pathways also modulate a wide range of autonomic functions i. Dopamine is known as the reward neurotransmitter, regulating pleasure, addiction, decision making, motivation, motor control 71 , and learning Dopaminergic areas include the ventral tegmental area, nucleus accumbens, hippocampus, amygdala, prefrontal cortex, substantia nigra, striatum, hypothalamus, and pituitary gland Figure 3. Role of neurosteroids in the modulation of the four main neurotransmitters.
Estrogen green and progesterone yellow interact with GABAergic, glutamatergic, serotonergic, and dopaminergic synapses at different levels: neurotransmitter synthesis, release, degradation, and neurotransmitter receptor synthesis, activation or inhibition 5HT, serotonin; MAO, monoamino oxidase; POA, preoptic area; PFC, prefrontal cortex. Estrogen potentiates release of glutamate and acts on postsynaptic membranes via the positive modulation of the ionotropic NMDA receptor which is related to synaptic plasticity, learning, and memory Estrogen also increases the expression of this receptor and its sensitivity to glutamate, which then induces an increase of neuronal sensitivity to synaptic input through calcium influx Hence, glutamatergic potentiation by estrogen leads to an increase in neuronal excitability.
This has been presented as a mechanism through which estrogen generates morphological plasticity changes such as an increase in spine density in the hippocampus, amygdala, and prefrontal cortex PFC. The plasticity changes have been associated with the role that estrogen has in improving learning, memory, and other cognitive functions In the striatum and the PFC, the inhibition of GABAergic synapses promotes an increase in the synaptic transmission of glutamatergic and dopaminergic neurons 76 , Serotonergic synapses are regulated by estrogen at different levels, including the promotion of serotonin synthesis through an increase in tryptophan hydroxylase enzyme levels Additionally, estrogen inhibits serotonin degradation by monoamine oxidase, an enzyme with a central role in the catabolism of monoaminergic neurotransmitters 80 , and inhibits serotonin reuptake from the synaptic cleft back to the presynaptic neuron 81 , resulting in an increase in serotonin availability.
Also, estrogen increases serotonin receptor levels via gene expression 82 , and is reported to induce the increase of serotonin binding with the 5-HT receptor The fact that serotonergic transmission in limbic areas and emotional functions is potentiated by estrogen, strongly suggests a role of the latter in mood and emotional states in women Finally, estrogen increases dopamine synthesis and decreases its degradation, reuptake, and recapture.
It also upregulates dopaminergic receptors 67 , The effect of estrogen on the dopaminergic system is of significant importance in the PFC, a region with high amounts of estrogen compared to other cortical areas 84 , 85 , where the presence of this neurosteroid impacts working memory function by affecting dopamine levels Also, through these actions, estrogen protects certain cognitive functions in the presence of stress in menopausal women 86 , Furthermore, through its effects on PFC and limbic regions such as the nucleus accumbens , estrogen influences emotional and motivational behaviors, for example by decreasing impulsive behaviors 21 , Progesterone and allopregnanolone have an inhibitory role upon glutamatergic synapses In the PFC, the progesterone metabolite allopregnanolone inhibits dopamine induced glutamate release 90 , a mechanism that may be of special importance in relating the effects of progesterone to cognition and neuropsychiatric diseases Allopregnanolone also inhibits glutamate release through an inhibition of the L-type Calcium channel It has been observed that allopregnanolone, through the potentiation of GABAergic synapses, leads to a decrease in glutamate receptor efficiency 93 , Through some of these mechanisms, progesterone decreases neuronal excitability in glutamatergic projections.
For this reason allopregnanolone has been attributed as having anti-anxiety effects similar to those of benzodiazepines and other positive modulators of GABA-A receptors 96 , Also, decreased circulating allopregnanolone levels are associated with depression in humans, and antidepressant treatment is associated with an increase in this metabolite 11 , With regard to its possible effects on cognition, the interaction of progesterone with GABA receptors in the hippocampus could give a reasonable explanation for why exogenous administration of progestins has a negative impact on the performance of healthy women in working memory tests When administered after an estrogen dose, progesterone increases serotonergic neurotransmission in the preoptic area of the hypothalamus POA However, in the ventromedial area of the hypothalamus, administration of estrogen, and progesterone reduces serotonin release Other studies show that progesterone decreases serotonergic neurotransmission by decreasing the expression of serotonin receptors and increasing serotonin degradation through monoamine oxidase B Furthermore, the stimulating effect of progesterone on serotonin release in POA could be associated with a decrease in copulatory behavior Thus, the coordinated action of estrogen followed by progesterone, would enhance serotonergic synaptic activity, while isolated progesterone would inhibit it, depending on the brain region.
Progesterone, as well as allopregnanolone, interacts with dopaminergic systems , In the striatum and POA, progesterone can stimulate dopamine release only if there has been a preexposure to estrogen , In the striatum, this action could be associated with the observed improvement in sensorimotor functions during phases of the menstrual cycle when progesterone is elevated In the POA this action may mediate some influence on maternal behavior In the nucleus accumbens, allopregnanolone has a largely positive modulatory effect over the release of dopamine , which could have an impact on behaviors that lead to drug abuse, including depression In the PFC, allopregnanolone has an inhibitory effect on dopamine release , possibly related to the modulation of emotion during physiological and pathological conditions In this way, the effect of progesterone on dopaminergic systems would depend primarily on the previous priming by estrogen and on the location of its activity.
There are millions of women who take hormonal contraceptives on a daily basis, often starting at a young age, a time when sex hormones have important organizational effects on brain structure There are three main formulations for hormonal contraception: monophasic combination, multiphasic combination, and progestin-only formulations Figures 1G,H.
These can be administered either orally, by IM injections, subcutaneous implants, or through medicated intrauterine devices IUDs. Combined hormonal contraceptive pills by definition combine progestin with one of two types of estrogens, most commonly ethinyl estradiol, and less commonly ethinyl estradiol 3-methyl ether, otherwise known as mestranol. The term progestin refers to synthetic progesterone It is this component of oral contraceptives OCs that, through its binding with PRs at different levels, suppresses ovulation , In addition to its interaction with progesterone receptors, progestins can also interact with other steroid receptors such as the androgen receptor AR , estrogen receptor, glucocorticoid receptor, and mineralocorticoid receptor, because all of these receptor proteins exhibit a structural similarity Those progestins which exhibit relatively high affinity to the AR, generally belong to the first generation of synthetic progestins and are derived from testosterone Among these are medroxyprogesterone acetate MPA and norethynodrel.
Second generation progestins have high binding affinity for the AR, so they also have androgenic effects. In contrast, newer progestins have a strong progestational action and exert anti-estrogenic, antigonadotropic, and antimineralocorticoid effects with decreased androgenic activity Among these are third-generation progestins: desogestrel or gestodene, derived from levonorgestrel LNG.
Finally, fourth generation progestins exhibit partial antiandrogenic activity or even no activity via the AR Among these are drospirenone, a spirolactone derivative, and dienogest, derived from a non-ethinylated progestin. In a recent study, which included a total of 1. All types of hormonal contraceptives had a statistically significant association with depression among adolescents, with levonorgestrel-only products exhibiting the higher incidence rate Another publication of the same group has shown that OC users have an increase in the incidence of suicide attempts and actual suicide.
Unlike other studies, this study included young women and found that the relative risk RR for suicide attempt varied by age. RR estimates were 2. It should be noted that adolescents were more sensitive than older women to the influence of hormonal contraception with regard to first suicide attempt The greater effect of exogenous hormones on mood and suicidal attempts among adolescents can partially be explained by the fact that this is a period of neuronal plasticity 10 , that is, that hormone levels can induce changes in neurons and direct the architectural and structural functionality of the brain Two studies that have included a large number of long-term OC users more than 3 years showed that the percentage of women who reported experiencing depressive symptoms declined as the number of years of use increased.
In the study done by Duke et al. In the study done by Skovlund et al. This also suggests that women that present depressive symptoms or mood changes related to OC use will stop the use of these Furthermore, longitudinal studies regarding the effect that long-term use of hormonal contraception may have upon mood, should consider the different types of OC's and the reason for which women used these, since it has been shown that women who use OC's for reasons other than contraception, were 1.
This same group showed, with the same cohort , that levonorgestrel-containing OCs had negative effects on sexual function in young women diminishing sexual desire, arousal, and pleasure. On the other hand, orgasm, concern, responsiveness, and self-image were not significantly affected by them. Similar results can be observed in the long-acting subdermal implant systems, which release a continuous dose of levonorgestrel for 5—7 years.
This dose would have a suppressive effect on kisspeptin, GnRH, and LH, which would then lead to the inhibition of ovulation for prolonged periods of time This results in a decrease in the levels of endogenous estradiol and progesterone It has been reported that women users of LNG subdermal implants will develop mood disorders , and are more likely to report mood swings, nervousness, and depression than women using non-hormonal methods With regard to medicated IUDs, their mechanism of action has not yet been clearly defined , but disruption of ovulation has been reported in several studies This effect would lead to a hormonal imbalance which, added to the direct action LNG could have in brain cells, can explain mood disorders found in IUD users.
The Danish study mentioned above showed that in the 15 to year-old group a 3. Furthermore, administration of levonorgestrel in doses as those found in emergency contraception in primates during the follicular phase, can inhibit ovulation, as shown by the profound suppression of estradiol and the increase in cycle length from 32 to 52 days Studies done in sterilized women also showed that ovulation is generally inhibited or that short luteal phases are observed when LNG is administered in the early or late follicular phase, but not when administered during the LH peak.
This disruption on endogenous estradiol and progesterone balance, added to a possible direct effect on brain cells, depends on the phase of the cycle during which it is administered and could affect mood in women using emergency contraception — Further studies are needed in order to elucidate the effects of LNG, administered as emergency contraception, on mood in women.
These studies should consider the phase of the cycle, and the number of doses ingested. These results can be explained, as mentioned earlier, through the multiple ways in which progesterone and estrogens can influence neural cells. For example, exogenous progestin increases levels of monoamine oxidase, which decreases serotonin concentrations and thus potentially produces depressive symptoms, irritability, and mood disorders — The estrogen and progesterone hormonal profile of OC users differs from that of naturally cycling women Figure 1 ; endogenous levels are lowered and fluctuations are suppressed via negative feedback mechanisms Also, the administration of exogenous estradiol causes an increase of hepatic sex hormone-binding globulin SHBG , which translates into a decrease in the fraction of free estradiol, progesterone, and testosterone Both the decrease in the bioavailability of these steroids and the lack of cyclicity could explain mood deterioration and changes in brain activity observed in women that use combined OCs In addition, the increase of serotonin release stimulated by progesterone at the level of the POA nucleus in the hypothalamus would result in a decrease of copulatory behaviors Considering that the effect of progestins is similar to that of progesterone, this together with the increase of SHBG could explain the decrease in libido that has been reported with the use of OC's , The activity of progestins will differ depending on whether they are administered together with estrogen, administered after estrogen or administered without estrogen.
Therefore, when analyzing steroid hormone activity, not only the available concentration and its form of administration must be taken into account, but the formulation to be administered monophasic, multiphasic, or progestin alone should be considered as well.
Also, not all progestins act in the same way. MPA used in injectable formulations deserves special attention, since, as described earlier, many neuroprotective effects of progesterone seem to be mediated by its conversion into neuroactive metabolites, such as DHP and allopregnanolone.
It has been reported that MPA blocks the conversion of progesterone into allopregnanolone by inhibiting the ARK1C enzyme , possibly blocking progesterone's neuroprotective effects. This action should be taken into consideration when administering these kinds of preparations to women, since, and despite its benefits in the treatment of uterine bleeding, it may have serious deleterious effects on the myelination of neural cells. Hence, when considering the effect that exogenous hormones exert over the body, their impact on the CNS and their influence on mood, behavior, and cognition should be evaluated.
Life expectancy has increased from approximately 50 to 80 years, but the age of menopause in women is relatively fixed. Given this, a larger number of women will spend over one-third of their lives in the postmenopausal state.
Therefore, the repercussions of diminishing levels of estrogen on multiple aspects of women's health are relevant Hormone therapy HT protocols for perimenopausal women, or those at an early postmenopause stage, have been developed to correct symptoms and prevent diseases related to the decline in hormonal secretion.
Also, depression and cognitive impairment are associated with declining steroidal hormone levels, effects that can be reverted with proper HT 33 , However, HT prescription may be associated with a higher incidence of estrogen-sensitive cancers, heart disease, stroke, and venous thromboembolism.
Thus, it is appropriate to keep this under consideration when counseling menopausal women Goodnick et al. Other studies have shown an improvement in verbal memory, attention, and reasoning together with a reduction in the risk of dementia These results may be explained by estrogen's neuroprotective capacity combined with its role in synaptic systems that influence memory and cognition. Estrogens also have a neurotrophic action, as demonstrated by an increase in the number of dendritic spine formations in the amygdala, hippocampus, and the PFC , Collectively, functional magnetic resonance studies have shown that postmenopausal women under HT have greater activation, larger volume, and increased cerebral blood flow to the hippocampus an area known to be affected in major depressive disorder compared with non-users of HT HT will have pleiotropic effects that will vary according to the timing of initiation, the form of estrogen and of progestin used, the route of administration e.
Regarding time of initiation, a critical period or window of opportunity hypothesis has shown that neurons become insensitive to estrogens after long-term hormone deprivation 87 , According to this hypothesis, only the administration of estrogens during a critical period related to the cessation of ovarian function will render beneficial effects.
Estrogens given after this critical period could cause negative effects This would not permit estrogen to act via its classical and non-classical pathways Thus, during a critical period following the cessation of ovarian function, the presence or absence of estrogen permanently alters the CNS. The end result is that the presence of estrogen during the critical period has beneficial effects on brain function, and decreases the risk of neurodegeneration and cognitive impairment , With regard to the form of estrogens and progestins administered, the proportion of estrogenic forms differs during menopause compared to premenopause.
Initially, the proportion of estradiol E2 is approximately five times greater than that of estrone E1 Later, during menopause and postmenopause, E1 is the predominant form of estrogen. Thus, to mimic premenopausal physiology it is necessary to administer E2 in HT The transdermal use of E2 has shown a consistently positive impact on women's mood during their perimenopausal stage , When combined HT is indicated, it is important to consider the type of progestin utilized. As mentioned earlier, multiple studies have shown negative effects on the myelination of neural cells with MPA use 87 , A clear example of the importance of considering the timing and the type of estrogen and progestin administered is shown in the large multicenter WHI Women's Health Initiative randomized placebo-controlled trial 24 , — After an average follow-up of 4—5 years, the WHIMS Memory Study portion failed to observe any improvement in measures of global cognition or rates of either mild cognitive impairment or dementia in women taking combined HT compared with placebo 24 , These results can be partly explained by the lack of positive results that could endorse the use of CEE in postmenopausal women, the known adverse effects that MPA has upon myelination and the negative effects of estrogen administration out of the critical opportunity period.
The present review shows that fluctuations in steroid hormones, influenced by factors such as age and health status, have consequences at the level of CNS and PNS. Utilizing both classical and non-classical pathways, neurosteroids participate in the physiological regulation of neurogenesis, neuronal survival, synaptic function, and myelin formation, thus influencing neuronal plasticity.
Because of these effects, neurosteroids will have different modulatory actions, exerting control over mood, cognition, and behavior. Additionally, they have a neuroprotective role in relation to certain neurocognitive pathologies Figure 4.
Figure 4. The figure shows areas of the brain regulated by steroid hormones Top , and some of the effects found when a normal or abnormal balance between estrogen and progesterone is present Bottom PFC, prefrontal cortex. This must be taken into consideration when treating patients with pathologies that affect ovarian function, such as PCOS, hyperprolactinemia, or hypothalamic anovulation, among others; and also when a woman consults for changes in mood or cognition.
On the other hand, hormone therapy during menopause and hormonal contraceptives are two modes of treatment through which exogenous steroids are administered to women. When facing a need for the administration of exogenous hormones, the stage of life each woman finds herself in should always be considered. When treating adolescents, special care should be taken due to the temporal plasticity window. For example, there are conditions in young women, such as anorexia nervosa, during which the levels of estrogen and progesterone will be low.
In these cases, it is necessary, as part of the treatment, to administer hormones. The same can be said of conditions such as aging, during which steroidal hormone decline has been shown to have negative effects. Thus, through the scientific evidence analyzed in this review, it should be clear that, when an exogenous steroid therapy is indicated, the timeliness of its administration and the types of estrogen and progestin utilized must be precisely taken into account.
Finally, questions to consider in future investigations include: i in terms of the ovarian continuum, what patterns of ovarian activity will have negative effects on the nervous system, and what patterns will have positive effects?
Could they have positive effects? What is the effect of emergency contraception upon the adolescent brain? In summary, the activity exerted by steroid hormones on the nervous system emphasizes the notion that achieving hormonal balance is a useful tool in seeking the well-being of women.
Healthcare providers, as well as the general population, should be aware of this knowledge. JD and MA researcher and writer. NM assistant researcher. FS assistant researcher, image design manager. SM writer and proofreader. PV corresponding author, tutor research guide, writer and proofreader. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The handling editor is currently co-organizing a Research Topic with one of the authors PV, and confirms the absence of any other collaboration. Brown JB, Thomas A. Types of ovarian activity in women and their significance: the continuum a reinterpretation of early findings. Hum Reprod Update 17 — Rupprecht R, Holsboer F. Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives.
Trends Neurosci. Truss M, Beato M. Steroid hormone receptors: interaction with deoxyribonucleic acid and transcription factors. Endocr Rev. PubMed Abstract Google Scholar. Neuroactive steroids. Neuroactive steroids: state of the art and new perspectives. Cell Mol Life Sci. Peripheral neuroactive steroids may be as good as the steroids in the cerebrospinal fluid for the diagnostics of CNS disturbances.
J Steroid Biochem Mol Biol. Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology 65 — Pubertal hormones organize the adolescent brain and behavior. Front Neuroendocrinol. The organizing actions of adolescent gonadal steroid hormones on brain and behavioral development. Neurosci Biobehav Rev. Influence of sex steroid hormones on the adolescent brain and behavior: an update.
Linacre Q. Reproductive steroid regulation of mood and behavior. Compr Physiol. Nicoll RA. A brief history of long-term potentiation. Neuron 93 — Whitlock JR. Learning induces long-term potentiation in the hippocampus. Science —7. Brinton RD. Estrogen-induced plasticity from cells to circuits: predictions for cognitive function. Trends Pharmacol Sci. Estradiol rapidly modulates synaptic plasticity of hippocampal neurons: involvement of kinase networks.
Brain Res. Rapid modulation of synaptic plasticity by estrogens as well as endocrine disrupters in hippocampal neurons. Brain Res Rev. Structure-function behavior relationship in estrogen-induced synaptic plasticity. Horm Behav. How oral contraceptives impact social-emotional behavior and brain function. Trends Cogn Sci. A review and update of mechanisms of estrogen in the hippocampus and amygdala for anxiety and depression behavior.
Neuropsychopharmacology 31 — Endocrine factors in the etiology of postpartum depression. Compr Psychiatry 44 — Ovarian cycle effects on immediate reward selection bias in humans: a role for estradiol. J Neurosci. Menstrual cycle influence on cognitive function and emotion processing from a reproductive perspective.
Front Neurosci. Hampson E.
To understand the plasticity of steroid hormone action and appreciate the specificity of signaling by different classes of steroids, it is important to understand the evolution of receptors from a common ancestral protein. Evolving with unique specificity, steroid receptors gained distinct functions in physiology; the processes governed by each steroid receptor are discussed in this chapter.
General factors that influence steroid hormone action are also highlighted. Finally, the chapter examines studies that describe alternative modes of action for steroid hormones and their receptors, including interactions with other transcription factors and nongenomic effects mediated by second messenger signaling pathways.
The steroid hormone receptors belong to a large family of transcription factors called nuclear receptors. The structure of the steroid receptors is modular, with distinct domains. The steroid receptors contain a highly conserved DNA-binding domain, a moderately conserved ligand-binding domain, and less well-conserved amino- and carboxy-terminal domains. Phylogenetic analysis determined that the steroid receptors clustered separately from other ligand-dependent transcription factors.
The relatedness of the steroid hormone receptors reflects gene duplication and divergence. Steroid receptors belong to a larger family of structurally and evolutionarily related proteins called nuclear receptors , which are encoded by 48 genes in the human genome. Through alternative splicing and alternative translation initiation, it is predicted that these 48 genes could result in many more receptors in the human proteome.
All nuclear receptors, including steroid receptors, exhibit a modular structure composed of distinct domains Fig. Some receptors also contain a carboxy-terminal F domain. The primary structure of each human steroid receptor is shown, along with its physiologic ligand. Specific residues within the DNA-binding C and ligand-binding E domains play an important part in receptor dimerization, which is critical, because most nuclear receptors are only transcriptionally active as homodimers or heterodimers.
Finally, nuclear receptors have one or two regions called activation function 1 and 2 AF1 and AF2 , which are required to transactivate gene expression. Some nuclear receptors have defined natural ligands—such as the steroid hormones, thyroid hormones, retinoids, or vitamin D—but the ligand for some nuclear receptors has not yet been identified.
These receptors are therefore called orphan receptors. The finding that diverse compounds act as ligands for nuclear receptors and that some receptors have no apparent ligand led to the hypothesis that ancestral nuclear receptors were constitutive transcription factors that independently evolved the ability to bind ligand.
However, a second hypothesis posits that ancestral receptors were ligand-dependent transcription factors that evolved specificity for different ligands by gene duplication, mutation, and functional divergence. There are several lines of evidence that favors the latter hypothesis for the evolution of ligand binding in the steroid receptor family.
First, the primary, secondary, and tertiary structures of the ligand-binding domain of different steroid receptors are highly similar. Second, detailed sequence, structural, and functional analyses strongly support the hypothesis that the ancestral steroid receptor bound estrogens and specificity for other steroids evolved by serial and parallel duplications of the ancestral gene, mutation of nucleotides coding for specific amino acids, and structural and functional divergence of the paralogues.
Finally, steroid hormone receptors are nuclear receptors unique to the chordate lineage, indicating that they originated when the first chordates evolved. Phylogenetic analysis of the primary amino acid sequences of 73 steroid receptors from jawed vertebrates e. Maximum likelihood reconstructions of the ancestral amino acid sequence indicate that the first steroid receptor was probably an ER-like molecule Fig.
Duplication of the latter gene then produced a corticoid receptor—like protein and a receptor for 3-ketogonadal steroid—like molecules androgens, progestins, or both. Whereas these three steroid receptors i. The number of paralogues for other gene families, such as the homeobox Hox genes, supports the hypothesis that many genes were duplicated in parallel in the ancestor of jawed vertebrates.
Experiments deleting large regions of different steroid receptors have clearly shown that domain C is responsible for DNA binding and that domain E is responsible for ligand binding. Furthermore, domain swapping of the entire ligand-binding domain between different receptors has shown that this region determines specificity for particular classes of steroid hormone. Nevertheless, crystal structures of various steroid hormone receptors show that all ligand-binding domains fold into a highly homologous three-layered structure with a small ligand-binding pocket in the center.
This pocket is composed of roughly 30 amino acids that are in close proximity or make direct contact with hormones when bound to their cognate receptors. In agreement with structural studies, experiments using site-directed mutagenesis indicate that specific but minor changes of amino acids within the ligand-binding pocket can lead to dramatic changes in the hormone-binding specificity of steroid receptors. For example, the human PR, GR, and MR contain a conserved cysteine residue that appears to be critical for contacting the C20 keto group found in progestins, glucocorticoids, and mineralocorticoids.
Mutation of the corresponding threonine to cysteine in the AR reduces its affinity for androgens and allows the receptor to transactivate gene expression in the presence of progesterone and corticoids. Based on structure-function studies of this sort and phylogenetic analyses, Thornton proposed a series of relatively minor amino acid changes that may account for broad changes in hormone specificity during the evolution of steroid receptors.
Similar studies of the DNA-binding domain have defined the molecular basis for interactions between steroid receptors and particular DNA sequences. The DNA-binding domain of nuclear receptors contains two zinc fingers. The first finger interacts with the major groove of DNA, whereas the second is involved in receptor dimerization.
Mutation of three residues within a five-residue motif known as the Proximal box P box of the first zinc finger of the GR to the corresponding residues in ER changes the binding specificity from DNA sequences called glucocorticoid-responsive elements to estrogen-responsive elements, and vice versa Fig. Although the DNA-binding domain is very highly conserved among nuclear receptors, these residues are variable among different receptors, which may in part account for receptor-specific regulation of distinct sets of genes.
These examples illustrate that site-directed mutagenesis and fine-scale comparison of amino acid sequences among receptors, in the context of the tertiary structure of the DNA- and ligand-binding domains, can lead to testable hypotheses about the evolution of signaling and regulation of gene expression by different classes of steroids. The steroid hormone receptors have well-described functions in the reproductive tract but also critically regulate general physiology.
Transgenic animal models and mutations identified in humans have provided insight into the cell-specific activities of the steroid hormones. ER, PR, and AR are indispensable for reproductive function but also regulate nonreproductive aspects of physiology.
GR signaling is essential for life after birth, maintaining general physiologic homeostasis, and integrating the hypothalamic-pituitary-adrenal HPA axis with reproductive function. MR is required for electrolyte balance and fluid transport, where insufficiency or deficiency can lead to mortality. Steroid receptors have taken on distinct physiologic roles during evolution.
Although androgens, estrogens, and progestins are sex-typical hormones, they are not sex-limited, and they play a physiologic role in both sexes. In contrast, GR and MR principally govern general physiology including, development, immune function, cognition and behavior, cardiovascular health, electrolyte balance, and metabolic homeostasis.
In addition to mediating physiologic homeostasis, stress-induced and endogenous levels of glucocorticoids regulate fertility, whereas the role of mineralocorticoids in reproductive functions is not well defined. The ERs are products of different genes and demonstrate distinct expression patterns across tissues and cell types Table 5. Consequently, these two receptors regulate unique biological functions, which have been characterized in transgenic animal models.
The differences in ligand binding have been exploited for the benefit of various therapies selective ER modulators. However, exogenous estrogenic compounds are also able to interfere with endogenous ligand binding, resulting in aberrant activation or repression of ER function. One of the first examples of endocrine disruption by a synthetic estrogenic compound occurred when women were exposed to diethylstilbestrol DES during pregnancy.
Prenatal exposure was linked to reproductive tract cancers in offspring. Subsequently, other estrogenic endocrine disruptors have been studied with reported impacts on ER signaling that vary in severity and duration. In addition to their physiological role in regulating reproductive tract function, estrogens are a risk factor for the initiation and progression of breast cancer.
However, ER antagonists can slow or stop the growth of breast cancer by blocking estrogen-regulated gene expression. The carcinogenic effects of estrogen in breast tissue may, in part, be mediated by the induction of vascular endothelial growth factor VEGF , as tumor growth is generally dependent on angiogenesis and a steady blood supply. Mutations that inactivate BRCA1 and confer increased risk for breast cancer may be due to a loss of the ability to antagonize the actions of estrogen.
ER loss-of-function mutations are rare but have been reported in a small number of patients. The clinical phenotypes of these patients were comparable to the ER knockout mouse model. Females presented with amenorrhea, cystic ovaries, thin endometrium, and no breast development. The predominant phenotype of affected males was delayed bone maturation. Somatic mutations and genetic polymorphisms in the human ER are also associated with various disease states. For example, a number of ER mutations have been detected in breast cancer.
A high-frequency somatic mutation between D and E region in the ER was identified in breast hyperplasias and was found to enhance estrogen sensitivity when evaluated in vitro. Breast cancer cell models of two other common ER mutations, YS and DG, demonstrate that some mutations bestow ligand-independent gene regulation, growth, and resistance to ER modulators.
Moreover, polymorphisms identified in genomic ER binding sites have been predicted to alter global ER activity and contribute to breast cancer pathogenesis. These mutations and polymorphisms likely influence the progression of cancer as well as the response to treatment. Like estrogens, progestins are necessary for female fertility. The necessity of progesterone signaling for female fertility was demonstrated in a mouse model devoid of both PR isoforms.
The female PR knockout mice were infertile due to defects in mating behavior, ovarian follicle rupture, implantation, and uterine function. Females also displayed disrupted mammary gland development. In contrast to females, PR-deficient males appear normal, and fertility was comparable to that of wild-type males. The isoforms PR-A and PR-B are alike except for the addition of amino acids at the amino-terminal end of PR-B due to the utilization of an alternative translational initiation site.
These amino acids confer an ancillary activation function domain AF3 , which contributes to the functional differences between the two isoforms. Deletion of the PR-A isoform phenocopied the fertility defects described in PR null mice, whereas selective ablation of PR-B only affected mammary gland development. Overexpression of PR-A in the uterus also resulted in infertility due to disrupted embryo attachment, indicating that precise regulation over the spatiotemporal expression of PR-A is required for the establishment of pregnancy.
One of the primary functions of progesterone signaling in the uterus prior to implantation is to inhibit the early actions of estradiol. For example, estrogen signaling drives uterine epithelial cell proliferation. However, estrogen signaling also promotes the expression of PR in the uterus, which subsequently inhibits epithelial proliferation through paracrine signaling to allow embryo implantation.
Likewise, mucin 1 MUC1 , a cell surface glycoprotein that provides a protective barrier to the uterine epithelium, is induced by estradiol in the uterus. However, the preimplantation rise in progesterone levels leads to the downregulation of MUC1, which is necessary for the embryo to adhere, implant, and invade. PR also critically coordinates paracrine signaling across the stroma and epithelium during early pregnancy.
Progesterone target genes in the epithelium mediate downstream signaling events in the stroma, which are critical during embryo implantation and for postimplantation maintenance of pregnancy. The antiproliferative properties of progesterone in the uterus have been targeted for the treatment of endometrial cancer.
The standard treatment for endometrial carcinomas is often surgical. However, patient desire to preserve fertility has prompted the use of progestin hormonal therapy as an alternative treatment option with varied success. In uterine fibroids, benign tumors of the uterine smooth muscle, progesterone promotes growth by stimulating proliferation and hypertrophy. For this reason, selective progesterone receptor modulators with antagonistic activity have been evaluated as therapeutic agents for fibroids.
In accord with the finding that PR is necessary for development of the mammary ducts, progesterone signaling has also been shown to play a role in the pathogenesis of breast cancer. Progesterone regulates proliferation of the mammary epithelium through autocrine and paracrine pathways. One of the main paracrine factors mediating progesterone-induced proliferation is receptor activator of nuclear factor kappa-B ligand RANKL. The induction of mitogenic factors by progesterone also contributes to the maintenance and expansion of the mammary gland stem cells.
However, studies have also demonstrated that PR activation in certain types of breast cancer improved progression-free survival. The differential actions of progesterone may reflect the distinct cellular context of healthy and malignant tissue or the dose and specificity of the progestogen used. Androgens, the main male sex steroids, drive the differentiation of the male reproductive tract during development and are crucial for reproductive functions in the adult.
During development, the androgen-producing cells of the mammalian gonad arise from precursor cells in the interstitium to become Leydig cells in males and theca cells in females. Androgens produced by the fetal Leydig cells direct the development of the male external genitalia, vas deferens, and related structures from the wolffian ducts. In mouse models of disrupted androgen signaling, the wolffian ducts regress and female external genitalia develop. Likewise, mutations in the human AR, causing androgen insensitivity syndrome, result in a female phenotype in individuals who are genotypically male.
Mutations in AR have also been identified that lead to partial androgen insensitivity by disrupting AR-cofactor interactions. Studies with the AR-deficient mouse model also demonstrated a role for androgen signaling in female reproduction.
AR-null female mice undergo premature ovarian senescence due to follicle atresia. Subsequent analysis of the AR-null mice revealed defective luteinization of the preovulatory follicles. In agreement with the animal studies, AR gene mutations have been characterized in female patients with premature ovarian failure. In the testis, the primary target of androgen action is the Sertoli cell.
Mice with a targeted deletion of AR in Sertoli cells are infertile due to spermatogenic arrest at meiosis and impaired Sertoli cell barrier formation blood—testis barrier. AR has also been conditionally deleted from the Leydig cells, which caused spermatogenesis arrested at the round spermatid stage, empty and atrophied epididymides, and infertility. The Leydig cell—specific knockout mice also exhibited higher serum gonadotropin levels and lower serum testosterone levels.
These observations indicate that testicular AR signaling is required to maintain spermatogenesis. During normal spermatogenesis, germ cell apoptosis is a constant feature of the adult testis and is required to maintain homeostasis within the seminiferous tubule. Exposure to excess and insufficient levels of testosterone can cause testicular cell death. Subscribe to: Post Comments Atom.
Popular Posts. Brushing technique: Bass and Modified Bass Methods. There are 5 commonly used brushing techniques: Bass or modified bass, Charters, Modified Stillman, Rolling stroke and Modified stroke. Cranial Nerves Mnemonic Song. Abdominal aorta extends from aortic opening of diaphragm at the level of lower border of T12 to lower part of body of L4. Branches of Abd Viva Exam: Blunders and Pretentions Video. Viva Exams are one of the most stressful time for Medical students, while from other point, for the examiner the viva exams can be funny How to remember Portal vein anatomy?
Origin: Hepatic Portal Vein is formed by the union of Splenic vein and Superior mesenteric Vein behind the neck of pancreas at L1 verteb Pulsus Paradoxus- Correct technique of measurement. Systolic blood pressure normally falls during quiet inspiration in normal individuals. It is the accentuation of normal physiology where t