Fetal Developing Brain
Brain and Nerves

Author: Carlotta Casale
Date: 19/02/2012



Estradiol is the most potent and ubiquitous member of a class of steroid hormones called estrogens. Fetuses and newborns are exposed to estradiol derived from their mother, their own gonads, and synthesized locally in their brains. Receptors for estradiol are nuclear transcription factors that regulate gene expression but also have actions at the membrane, including activation of signal transduction pathways. The developing brain expresses high levels of receptors for estradiol. The actions of estradiol on developing brain are generally permanent and range from establishment of sex differences to pervasive trophic and neuroprotective effects. Cellular end points mediated by estradiol include the following: 1) apoptosis, with estradiol preventing it in some regions but promoting it in others; 2) synaptogenesis, again estradiol promotes in some regions and inhibits in others; and 3) morphometry of neurons and astrocytes. Estradiol also impacts cellular physiology by modulating calcium handling, immediate-early-gene expression, and kinase activity. The specific mechanisms of estradiol action permanently impacting the brain are regionally specific and often involve neuronal/glial cross-talk. The introduction of endocrine disrupting compounds into the environment that mimic or alter the actions of estradiol has generated considerable concern, and the developing brain is a particularly sensitive target. Prostaglandins, glutamate, GABA, granulin, and focal adhesion kinase are among the signaling molecules co-opted by estradiol to differentiate male from female brains, but much remains to be learned. Only by understanding completely the mechanisms and impact of estradiol action on the developing brain can we also understand when these processes go awry.

Estradiol content and estrogen receptors in developing brain:
Before considering the mechanisms and functional outcomes of estradiol action in the developing brain, it seems important to know if there is any, if so where, and if so how much? Most effects of estradiol require a receptor, so the levels and distribution of these critical proteins are of central interest. Steroids are distinct from peptides in that they are synthesized on demand, as opposed to stored, and for the most part they act on targets at a distance from the place of origin, although this concept has recently been challenged (19). Estradiol is derived from testosterone following aromatization of the A ring via the p450 enzyme aromatase, also called estradiol synthase.


• Estradiol Promotes Neurite Growth

Some of the earliest and most spectacular reports on estradiol effects on the developing brain were the landmark studies of Dominique Toran-Allerand and co-workers (216, 217, 219) on the profound induction of neurite outgrowth from organotypic explant cultures of the preoptic area, hypothalamus, and cerebral cortex.

Adding to the complexity is the nature of the estradiol action itself, which has been less than straightforward. Estradiol provided in the dish directly activates neurite growth, and at the time these discoveries were made, the late 1970s and early 1980s, the assumption was that ER acting at EREs would transcribe specific genes that would then direct neurite growth. Growth factors induced by estradiol trough glutamate action in a complex mechanism, such as nerve growth factor (NGF) and brain-derived nerve growth factor (BDNF), and structural proteins involved in neurite extension, such as growth-associated protein 43 (GAP-43) and microtubule-associated protein (MAP-2), were obvious candidates for upregulation by ER,. At the same time focal adhesion molecules are downregulated. the MAP kinase signaling pathway was also activated by estradiol in cortical neurons (124, 197).

• Estradiol Regulates Synaptic Patterning

As discussed above, one of the principle actions of estradiol on the developing rodent brain is to precondition the neural network so that adult hormonal secretions can activate the correct response. To do so, estradiol is a potent modulator of the formation of dendritic spines, the major site of excitatory glutamatergic synapses.. Estradiol is also capable of modulating dendritic spine formation in the adult brain, and this has generated considerable interest, particularly in the hippocampus where spine formation is synonymous with plasticity associated with learning and memory. But there are several important and perhaps informative differences between estradiol induction of dendritic spine synapses in the adult versus the neonate. First is the magnitude of the effect. In adult female hippocampus, estradiol induces at maximum a 30% increase in the density of dendritic spines (244), and in the hypothalamus, the effect is even smaller (41).

In contrast, in the neonatal preoptic area or hypothalamus, estradiol increases dendritic spines by 200–300%. Second is that estradiol-induced spines in the adult are transient, when the estradiol disappears so do the spines, but in the neonate, the density of spines that are formed within the first few days after birth will persist into adulthood (5,127). These differences suggest that both the mechanism and the function of estradiol-induced spine synapse formation are fundamentally different in the developing as opposed to mature brain. Information we have to date would support this view, although no direct empirical evidence has been generated, reflecting more the separation of investigator focus than technical or biological limitations. The current state of understanding for each region investigated is reviewed here.



The rate-limiting enzyme in GABA synthesis, GAD, is found only in neurons, thus establishing this cell type as the likely primary site of estradiol action where it increases the activity of GAD, and thereby the synthesis of GABA, which is released from neurons to act on neighboring astrocytes to induce stellation. Astrocytes express GABAA receptors and, due to relatively high intracellular chloride, respond with membrane depolarization and an influx of calcium. Activation of GABAA receptors on immature cortical astrocytes induces differentiation and stellation (69, 147), an effect consistent with that observed in the arcuate nucleus. Calcium influx is citotoxic because it lead to energetic cost to re-establish previuos cell condition. some neurons provided with a particular estradiol pattern receptor shows a massive release of gaba that induce a massive calcium influx that causes cell death mediated by high level of bcl2 and caspase 3 expression; other receptor patterns let cell survival: moreover these survived cells are proved to be stronger than the others that hasn’t been exposed to estradiol effect.

Depolarizing GABA in fetal brain

FIG. 8. Estradiol enhancement of depolarizing GABA action. The normally inhibitory transmitter GABA is predominantly excitatory in the developing brain due to a shift in the reversal potential for chloride so that activation of GABAA receptors results in chloride efflux and membrane depolarization as opposed to hyperpolarization. The membrane depolarization induced by GABA is sufficient to activate voltage-gated calcium channels and promote calcium influx. This excitatory effect of .GABA is linked to trophic actions and promotes the maturation of synapses. Estradiol enhances the excitatory actions of depolarizing GABA by increasing the magnitude of the calcium influx, increasing the number of neurons that respond to GABA as depolarizing and extending the developmental duration of depolarizing GABA. The principle action of estradiol is to increase the amount and activity of the sodiumpotassium- chloride cotransporter NKCC1 that maintains intracellular chloride. This transporter is expressed at high levels in mature neurons but gradually declines as development proceeds and is superceded by another transporter, KCC2, which transports chloride out of the cell. A potential deleterious consequence of the estradiol-induced enhancement of depolarizing GABA is a lowering of the threshold to excitotoxicity in the imm ature brain.

Estradiol Is Damaging: fetal apoptosis and epilepsy in adult life
APOPTOSIS:Unlike the damage induced by glutamate, excessive activation of GABAA receptors induced widespread cell death in the hippocampus in both males and females, although the damage was slightly but significantly greater in males (150, 151). The damage induced was enduring and compromised performance on cognitive tasks later in life . Cell death was correlated with expression of genes associated with the apoptotic cascade, such as caspase-3 and BCl2, and was prevented by pretreatment with an L-type voltage-gated channel blocker, thus confirming the classic excessive calcium-induced excitotoxic pathway of cell death In addition, testosterone induced different concentration-dependent Ca2+ signaling patterns: at low concentrations of testosterone (100 nm), Ca2+ oscillations were produced, whereas high concentrations (1-10 μm) induced a sustained Ca2+ increase. Elevated testosterone concentrations increase cell death, and this effect was abolished in the presence of either inhibitors of caspases or the inositol 1,4,5-trisphosphate receptor (InsP3R)-mediated Ca2+ release. Knockdown of InsP3R type 1 with specific small interfering RNA also abolished the testosterone-induced cell death and the prolonged Ca2+ signals. In contrast, knockdown of InsP3R type 3 modified neither the apoptotic response nor the Ca2+ signals. These results support our hypothesis that elevated testosterone alters InsP3R type 1-mediated intracellular Ca2+ signaling and that the prolonged Ca2+ signals lead to apoptotic cell death. These effects of testosterone on neurons will have long term effects on brain function
EPILEPSY:studies suggest that estrogens have exclusively proconvulsant properties, it has now become clear that estrogens also produce anticonvulsant effects. These opposite effects of estrogens on seizures may depend on treatment duration, latency prior to seizure testing, mode of administration, estrogen dose and hormonal status, estrogenic species, the region/neurotransmitter system involved, seizure type/model used, and sex.
Hormonal therapy for epilepsy

Glutamate receptor activation is just onestep in a complex process that begins with estradiol upregulation of the enzyme cyclooxygenase-2, or COX-2, the inducible form of COX and a nodal point in the production of prostaglandins and the thromboxanes (95). Induction of COX-2 is strongly yoked with an inducible form of prostaglandin E2 synthase, mPGEs, leading to the preferential production of PGE2 over other prostanoids. Estradiol treatment of neonatal female rats increases PGE2 levels in the preoptic area in hypothalamus by sevenfold, and this appears to be a direct result of estradiol induction of COX-2 gene transcription (5).. There are two effects of PGE2 on neurons: increased stellation of astrocites (6) and release of glutamate (32, 187).

The glutamate released in response to PGE2 is speculated to then activate AMPA receptors on the neighboring (ororiginating) neuron to induce formation of dendritic spines (Fig. 5). The functional impact of PGE2 production and formation of spines in the newborn male brain will be discussed below. glutamate , trough a not so well known mechanism involving its receptors, promotes transcription of ngf, glutamine expression and reduces transcription of focal adhesion molecule glutamate reduces both FAK and paxillin in the newborn brain, and expression of both of these proteins
is positively associated with a reduction in neurite growth
and branching (199). Thus estradiol can promote dendritic
extension by reducing FAK and paxillin
Demonstration :
fans administration during pregnancy are proved to overcome placente barrier causing inhibition of cox in fetal growing neurons
Use of non-steroidal anti-inflammatory drugs in pregnancy: impact on the fetus and newborn

Estradiol Is Protective: calmoduline fetal production
In the adult brain, hypoxia/ischemia induces massive release of glutamate into the extracellular space, initiating an excitotoxic cascade due to excessive influx of calcium through NMDA receptors and voltage-gated calcium channels (29, 48). The same is true for the immature brain in regards to excessive release of glutamate, but the effects of glutamate are not the same in the immature brain as in the adult. This appears to be due to both the population and functionality of glutamate receptors being distinctly different in the developing brain. Estradiol levels are elevated in the hippocampus at birth,1 gradually declining over the first week of life. A potential but untested source of the relative imperviousness of the neonatal hippocampus to glutamate-mediated excitotoxicity could be this endogenous neuroprotective steroid

to reveal the secret of
how estradiol and glutamate save the cells. Other than being distinguished
by their high levels of calmoduline expression (193),
a calcium binding protein, means that some neurons are
preferentially saved by estradiol.Calmoduline is proved to have long-term neuroprotective action

• estradiol is synthesized de novo by the developing brain

Steroidogenesis requires the transport of cholesterol into the inner mitochondrial membrane by steroidogenic acute regulatory protein (StAR), and the subsequent conversion to pregnenolone by the P-450scc enzyme CYP11. Both of these have been detected at high levels in hippocampal pyramidal neurons, along with picomolar levels of pregnenolone and its sulfated derivative (108). Conversion of pregnenolone to progesterone, as well as dehydroepiandrosterone (DHEA), requires 3_-hydroxysteroid dehydrogenase (3_-HSD). Developmentally, the expression of 3_-HSD is at its highest level in newborn hippocampus and declines with increasing age. Concentrations of hippocampal pregnenolone and progesterone measured by gas chromatography/mass spectrometry were also at their highest on the day of birth and exceeded those found in plasma, suggesting local synthesis (102). Other studies confirm the presence of 3_-HSD as well as 5_-reductase and 21-hydroxylase (102, 135, 189,
202). Allopregnanolone, a 5_-reduced metabolite of dihydroprogesterone, as well as DHEA have also been detected at low levels in the brains of adult adrenalectomized and gonadectomized male rats (47, 183). Cultured astrocytes and neurons from neonatal rodent cerebral cortex are capable of synthesizing DHEA and subsequently converting the steroid to testosterone and ultimately estradiol (248).

In situ hybridization detection of .CYP19 (aromatase) mRNA reveals high levels in POA, hypothalamus, and amygdala, with moderate levels in the hippocampus (227, 228). Activity assays reveal the same pattern in explants or cultured neurons of neonatal rat and mouse brain. The highest levels of estradiol production from [3H]androstenedione are found in the diencephalic brain regions, but the neonatal hippocampus appears to make up to half that seen in these sexually dimorphic brain regions (122). Interestingly, the hippocampus and cortex are distinct from sexually dimorphic brain regions in not exhibiting aromatase activity until shortly after parturition (122). A critical enzyme, CYP17, required for the conversion of pregnenolone to DHEA had long eluded detection in the adult brain, despite measurable levels of DHEA, until a recent report detecting it in adult male hippocampus. Given one accepts the developing brain is making its own estradiol, the next obvious question is, Why? There must be important functional benefits if such an energetically . Estradiol has potent neuroprotective effects in the adult brain, and this is true in some instances in the developing brain as well (see below). Neuroprotection is an attribute of benefit to both males and females; thus this may be the primary ultimate causation for estradiol synthesis in the developing telencephalon of both males and females, but how this is achieved proximately is not known.

Estradiol and the Developing Brain

•first days of life are essential for good brain development- neoronal problems due to caesarian section

Long-lasting effects of perinatal asphyxia on exploration, memory and incentive downshift

The cytochrome P450 superfamily (officially abbreviated as CYP) is a large and diverse group of enzymes. The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances such as drugs and other toxic chemicals. CYPs are the major enzymes involved in drug metabolism and bioactivation, accounting for about 75% of the total number of different metabolic reactions.1
The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom of oxygen into an organic substrate (RH) while the other oxygen atom is reduced to water:
RH + O2 + NADPH + H+ → ROH + H2O + NADP+
Human CYPs are primarily membrane-associated proteins12 located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells. CYPs metabolize thousands of endogenous and exogenous chemicals. Some CYPs metabolize only one (or a very few) substrates, such as CYP19 (aromatase), while others may metabolize multiple substrates. Both of these characteristics account for their central importance in medicine. Cytochrome P450 enzymes are present in most tissues of the body, and play important roles in hormone synthesis and breakdown (including estrogen and testosterone synthesis and metabolism), cholesterol synthesis, and vitamin D metabolism. Cytochrome P450 enzymes also function to metabolize potentially toxic compounds, including drugs and products of endogenous metabolism such as bilirubin, principally in the liver.

Cytochrome P450

• molti farmaci inducono o inibiscono cyp450---aloperidolo---no steroidogenesi e no colosterolo—problemi se dati in gravidanza
Clozapine or Haloperidol in rats prenatally exposed to methylazoxymethanol, a compound inducing entorhinal-hippocampal deficits, alter brain and blood neurotrophins' concentrations


That males have an X and a Y chromosome and females two X chromosomes has only been known for a little over 50 years, and it wasn’t until 1990 that the critical gene on the Y chromosome, SRY, for the differentiation of testis from the bipotential gonad, was finally isolated and sequenced (111). The expression of SRY is initiated within the first days or weeks of pregnancy (rodent versus human), and with this single event, the ultimate state of the organism’s sex is determined. In the absence of SRY, regardless of how much else of the Y chromosome is present, the gonad will develop into an ovaryThus the female developmental pathway is the default, but the establishment of sex as female is no less determinant than the establishment of sex as male. Once gonadal sex is established it will guide the formation of the appropriate urogenital tract. The Wolffian duct system will survive and become the vas deferens and associated secretory glands of the male reproductive system while actively suppressing the formation of the female system. Conversely, if the gonad becomes an ovary, the male system will degenerate due to insufficient androgen and the Mullerian duct system will develop into the female reproductive tract. Differentiation of external genitalia and secondary sex characteristics are then progressively established by gonadal steroid synthesis at the appropriate time in life. In humans, the process of sex determination and formation of external genitalia is complete by the 13th week of gestation, a remarkably early event in the 40-wk process. Sex determination is therefore the process leading to formation of all things we generally associate with gender but really are a reflection of sex. Sex differentiation of the brain, by contrast, is a separate process that is largely driven by gonadal steroids during a later developmental period and in humans may relate to self-perception of gender. The impact of steroids is restricted to a sensitive window, which is mid to late gestation in primates, as best we can tell, and just before and after birth in rodents. This process is multi-faceted, impacting on reproductive behavior and physiology as well as many non-reproductionrelated processes via distinct mechanisms in separate brain areas and often with varying sensitive periods. Of the many contributing variables to the complex process of brain sex differentiation, one of the most potent and prevalent is estradio

• The Aromatization Hypothesis in Brain Sex Differentiation

At approximately the same time that morphometric sex differences were being described in the avian and mammalian brain, another mystery of sexual differentiation was also being resolved. In early studies on the organizational/activational hypothesis in rats, testosterone was administered to newborn females to masculinize the brain. As a control for the steroid injection, newborn females were also treated with estradiol. To everyone’s surprise, estradiol was not only effective at masculinizing the brain, it was more effective than testosterone. Administering the nonaromatizable androgen dihydrotestosterone (DHT), which potently activates androgen receptors, was largely ineffective (239). These results were difficult to reconcile with two things: first was the notion that activation of the male testis during perinatal development was the basis for masculinization, and second was that during pregnancy estradiol production by the placenta results in maternal levels of estradiol so high that there would clearly be exposure of all of the fetuses, precluding any differential exposure in one sex over theother. The latter problem could be explained by the presence of _-fetoprotein, a circulating binding globulin found in late-gestation fetuses and early postnatal pups that has a high affinity for estradiol and thereby sequesters the steroid in the bloodstream, preventing it from masculinizing the brain. The former issue, of what is the role of 2testosterone, was explained by the discovery that the brain is a major producer of the P-450 enzyme aromatase, also called estradiol synthase as it converts testosterone into estradiol (115). Not only is aromatase expressed by neurons in the brain, it is expressed at its highest level in the sexually dimorphic regions of the preoptic area and hypothalamus during the perinatal sensitive period (77, 104, 113, 185, 227, 228). Aromatase is also found in the telencephalon, but at much lower levels than the diencephalon (122). Together, these observations formed the basis of the aromatization hypothesis; perinatal fetuses and pups are protected by maternal estradiol via the binding capacity of the _-fetoprotein in their circulation, and testicularly derived testosterone diffuses into the male brain where it is locally aromatized to estradiol; estradiol then initiates the process of masculinization.However, the importance of _-fetoprotein in protecting female fetuses from behavioral masculinization and infertility at the hands of maternal estrogens is definitively established by observation of both those end points in female neonates with a null mutation rendering them incapable of _-fetoprotein production
alpha f.etoprotein and related pathologies
is a protein1[2] that in humans is encoded by the AFP gene.3[4]AFP is a major plasma protein produced by the yolk sac and the liver during fetal development that is thought to be the fetal form of serum albumin. The AFP gene is located on the q arm of chromosome 4 (4q25). AFP binds to copper, nickel, fatty acids and bilirubin4 and is found in monomeric, dimeric and trimeric forms.The human fetus has the highest amount of AFP levels found in humans. At the end of the first trimester, fetal AFP levels decrease. Normal adult levels are usually achieved by the age of 8 to 12 months.; however, in fetuses it binds estradiol to prevent the transport of this hormone across the placenta. AFP is measured in pregnant women through the analysis of maternal blood or amniotic fluid, as a screening test for a subset of developmental abnormalities: it is principally increased in open neural tube defects and omphalocele & decreased in Down syndrome.. In rats, AFP binds maternal estrogen, preventing its passage through the placenta. The main function of this is to prevent the masculinization of female fetuses. The system can be overridden with massive injections of estrogen, which swamp the AFP system and masculinize female fetuses.

General reaction for the conversion of testosterone to estradiol catalyzed by aromatase. Steroids are composed of four fused rings (labeled A-D). Aromatase converts the ring labeled "A" into an aromatic state.

Catalytic mechanism of aromatase. The methyl group is a oxidized and subsequently eliminated.2
Aromatase excess syndrome
A number of investigators have reported on a rather rare syndrome of excess aromatase activity. In boys, it can lead to gynecomastia, and in girls to precocious puberty and gigantomastia. In both sexes, early epiphyseal closure leads to short stature. This condition is due to mutations in the CYP19A1 gene which encodes aromatase.6 It is inherited in an autosomal dominat fashion.7 It has been suggested that the pharaoh Akhenaten and other members of his family may have suffered from this disorder.8 It is one of the causes of familial precocious puberty - a condition first described in 1937.9
Aromatase deficiency syndrome
This syndrome is due to a mutation of gene CYP19 and inherited in an autosomal recessive way. Accumulations of androgens during pregnancy may lead to virilization of a female at birth (males are not affected). Females will have primary amenorrhea. Individuals of both sexes will be tall, as lack of estrogen does not bring the epiphyseal lines to closure.
Aromatase inhibitors
Main article: Aromatase inhibitor
The inhibition of the enzyme leads to profound hypoestrogenism (low estrogen levels). Thus, aromatase inhibitors have become useful in the management of patients with breast cancer whose lesion was found to be estrogen receptor positive. An example of an aromatase inhibitor is letrozole, marketed originally under the name 'Femara.' Aromatase inhibitors are also beginning to be prescribed to men on testosterone replacement therapy as a way to keep estrogen levels from spiking once doses of testosterone are introduced to their systems.
Extracts of certain (white button variety: Agaricus bisporus) mushrooms have been shown to inhibit aromatase in vitro

• Estradiol :Volumetric Sex Differences : Sexually dimorphic nucleus

Estradiol modulation of naturally occurring cell death in the developing brain is limited to very specific regions and can have opposing effects, sometimes promoting cell survival, and sometimes orchestrating a cell’s demise.


The medial preoptic area (POA) is the major brain site controlling adult male sexual behavior and female maternal behavior and is thus not surprising as a site of major sex differences in morphometry. The SDN has already been discussed, but in addition to this remarkable volumetric difference, the same region also boasts a sex difference in dendritic spine synapses, with males having two- to threefold higher levels than females (7, 209). Again, as in the arcuate nucleus, the induction of spines is permanent, with the pattern established in the first few days persisting until at least 90 days of age (5). There is also a sex difference in the morphometry of astrocytes in the POA, with again males having more complex, stellate astrocytes than females (6).

In rats, the celebrated sexually dimorphic nucleus (SDN) in POA is the poster child for sex differences in the brain. .It is five to seven times larger in males than females and situated right in the heart of male-sex-behavior-central, the preoptic area (134). The SDN both sends and receives a wide-ranging array of inputs, suggesting it serves as integrative node for variables regulating expression of male sex behavior, but such a function is hard to demonstrate.. The SDN is a dense collection of neurons in the medial preoptic nucleus. The volume of the SDN can be quantified by sectioning and staining the brain, tracing the area consisting of dense cells and reconstructing the area based on slice thickness and magnification. The density of cells does not differ in males and females, but the number and therefore the area occupied does. Males and females start out with the same number of neurons destined to become part of the SDN, but beginning about postnatal day 3 and peaking on postnatal day 7, cells in the female die at a prolific rate. By 10 days of life, it’s game over, the final volume of the SDN is forever established. If females are .treated with either estradiol or aromatizable androgen sufficiently early, the cells will not die, and despite the absence of estradiol later, the female will always have a male-sized SDN.


The anteroventral periventricular nucleus (AVPV) is notably in contrast to the SDN in that this nucleus is larger in females, and this is entirely due to the ability of estradiol to kill off cells (195). The AVPV also offers several advantages over the SDN, with the two most important being that it is present in mice and its functional significance is clear, it is a critical node in the control of the surge of gonadotropin secretion required for ovulation. Moreover, the AVPV is part of a well-defined sexually dimorphic circuit. A substantial portion of the neurons in the AVPV are dopaminergic, and it is their survival that is primarily undermined by estradiol. The use of single- and double-knockout mice suggests that both isoforms of ER are required for the full male AVPV phenotype to be achieved (35), an interesting contrast to the SDN which uses only ER_ to regulate cell death. The functional involvement of both isoforms is confirmed with the use of ER_ and ER_ selective agonists, either of which when given neonatally to females will reduce AVPV volume and impart infertility due to impaired cyclicity (160). That roughly identical results are found in rats and mice and the unusual nature of the estradiol action (i.e., killing cells, or at least preventing them from surviving) and the requirement for both receptor isoforms, should provide a good hook from which to begin to investigate the specific cellular mechanisms by which estradiol is acting.
difference in AVPV nucleus is linked with the difference in releasing LH in male and female brain
Yet these neurons preside over the most marked of sexually dimorphic responses, the pattern of LH release from the anterior pituitary. In males, LH is pulsatile and regular, with a peak every 30 min to a few hours depending on the species. In females, this pulsatile pattern is disrupted by a mid-cycle surge in LH that is required for ovulation

Onuf’s nucleus is a distinct group of neurons located in the ventral part (laminae IX) of the anterior horn of the sacral region of the human spinal cord involved in the maintenance of micturition and defecatory continence, as well as muscular contraction during orgasm. It contains motor neurons, and is the origin of the pudendal nerve. was considered distinct by Onufrowicz because the cells were different in size from the surrounding neurons in the anterolateral group, suggesting that they were independent. . Sexual dimorphism of Onuf’s nucleus has been found in dogs, monkeys, and humans. Males of these species have more of these motoneurons than do their female counterparts. It has also been shown that the sex differences in Onuf’s nucleus can be reduced (or in some cases eliminated) by exposing a prenatal female to high levels of androgen
Onuf's nucleus's_nucleus

refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands (steroidogenesis).1 CAH is one of the possible underlying synthesis problems in Addison’s disease. CAH is a genetic disorder in which girls are masculinized because the adrenal glands secrete large amounts of androgen during prenatal development. The extra androgen does not affect a baby boy's physical development, but in baby girls it can enlarge the clitoris so that it resembles a penis. The girls sometimes have surgery during infancy to correct their physical appearance, although this practice is highly controversial, and they can receive hormone therapy to correct the imbalance of androgen. During childhood and adolescence, girls with CAH prefer masculine activities and male playmates to a much greater extent than girls not exposed to these amounts of androgen. [2]Most of these conditions involve excessive or deficient production of sex steroids and can alter development of primary or secondary sex characteristics in some affected infants, children, or adults.3
Classification: Cortisol is an adrenal steroid hormone that is required for normal endocrine function. Production begins in the second month of fetal life. Poor cortisol production is a hallmark of most forms of CAH. Inefficient cortisol production results in rising levels of ACTH, which in turn induces overgrowth (hyperplasia) and overactivity of the steroid-producing cells of the adrenal cortex. The defects causing adrenal hyperplasia are congenital (i.e., present at birth).

Cortisol deficiency in CAH is usually partial, and not the most serious problem for an affected person. Synthesis of cortisol shares steps with synthesis of mineralocorticoids such as aldosterone, androgens such as testosterone, and estrogens such as estradiol. The resulting excessive or deficient production of these three classes of hormones produce the most important problems for people with CAH. Specific enzyme inefficiencies are associated with characteristic patterns of over- or underproduction of mineralocorticoids or sex steroids.
Since the 1960s most endocrinologists have referred to the forms of CAH by the traditional names in the left column, which generally correspond to the deficient enzyme activity. As exact structures and genes for the enzymes were identified in the 1980s, most of the enzymes were found to be cytochrome P450 oxidases and were renamed to reflect this. In some cases, more than one enzyme was found to participate in a reaction, and in other cases a single enzyme mediated in more than one reaction. There was also variation in different tissues and mammalian species.
In all its forms, congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for about 95% of diagnosed cases of CAH. Unless another specific enzyme is mentioned, "CAH" in nearly all contexts refers to 21-hydroxylase deficiency. (The terms "salt-wasting CAH", and "simple virilizing CAH" usually refer to subtypes of this condition.) CAH due to deficiencies of enzymes other than 21-hydroxylase present many of the same management challenges as 21-hydroxylase deficiency, but some involve mineralocorticoid excess or sex steroid deficiency.
Congenital adrenal hyperplasia

From the 1940s until 1971, a common medical practice for maintaining a healthy pregnancy was the treatment of pregnant women with the highly potent estradiol analog diethylstilbesterol (DES). The practice was discontinued when it became evident that aughters of DES-treated mothers had an increased incidence of clear cell adenocarcinoma of the vagina and cervix. Interest in the psychosexual effects of DES exposure in women followed the reports of estradiol being the masculinizing factor of the male rodent brain. Early reports of psychosis (107) and lack of interest in parenting (63) in DES-exposed girls were not replicated in subsequent larger studies (118, 146), including ones by the same group of scientists. In hindsight, the lack of effect of DES on brain differentiation of human females is consistent with empirical results generated in primates in which most results indicate no important role for estrogens in masculinization, this function instead being performed by prenatal androgens combined with social context and rearing conditions.


5-alpha-reductase deficiency

5-alpha reductase produces dihydrotestosterone

5-Alpha-reductase deficiency (5-ARD) is an autosomal recessive intersex condition caused by a mutation of the 5-alpha reductase type 2 gene.1
Normal function:5-Alpha-reductase is an enzyme that converts testosterone to dihydrotestosterone (DHT) in peripheral tissues. 5-Alpha-reductase deficiency-2 is biochemically characterized by low to low-normal levels of testosterone and decreased levels of 5α-DHT, creating a higher testosterone/DHT ratio.

Biochemical effects of 5-alpha-reductase deficiency-2 in testosterone biosynthesis. Levels of testosterone are elevated, while levels of DHT are significantly decreased, leading to male undervirilization.
DHT is a potent androgen, necessary for the development of male external genitalia in utero.
Signs:The condition affects only genetic males (that is, those with a Y-chromosome) because DHT has no known role in female development.2
Individuals with 5-ARD can have normal male external genitalia, ambiguous genitalia, or normal female genitalia. They are born with male gonads, including testicles and Wolffian structures, but usually have female primary sex characteristics. As a consequence, they are often raised as girls, but usually have a male gender identity.3[4].
At puberty, individuals often have primary amenorrhoea, and may experience virilization. This may include descending of the testes, hirsutism (facial/body hair considered normal in males - not to be confused with hypertrichosis), deepening of the voice, and enlargement of the clitoris.
5-alpha-reductase deficiency

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