Androgen insensitivity syndrome ( AIS ) is a condition characterized by the inability to respond to androgens, usually due to androgen receptor dysfunction. It occurs in 1 in 20,000 to 64,000 XY ( karyotypically male) births. This condition leads to a partial or complete inability of cells to respond to androgens . This lack of response can hinder or prevent the development of male genitals , as well as affect or inhibit the development of male secondary sexual characteristics during puberty . It does not significantly affect female genital or sexual development. Androgen insensitivity is clinically relevant only in genetic males, (i.e., individuals with a Y-chromosome , or more specifically, an SRY gene ). Clinical phenotypes in these individuals can range from a typical male habitus with mild spermatogenic issues or reduced secondary terminal hair , to a complete female habitus , despite having a Y-chromosome. AIS is classified into three categories based on the degree of genital masculinization : Mild androgen insensitivity syndrome (MAIS) is indicated when the external genitalia are typically male (a penis and a scrotum ). Partial androgen insensitivity syndrome (PAIS) is indicated when the external genitalia are partially, but not fully, masculinized . Complete androgen insensitivity syndrome (CAIS) is indicated when the external genitalia resemble those of a typical female (a vulva ) Androgen insensitivity syndrome is the most common cause of 46,XY undermasculinized genitalia . Management of AIS is currently focused on symptomatic management ; there is no available method to correct the defective androgen receptor proteins caused by AR gene mutations. Management areas include sex assignment , genitoplasty , gonadectomy to lower tumor risk, hormone replacement therapy , genetic counseling , and psychological counseling . Genetics The human androgen receptor (AR) is a protein encoded by a gene located on the proximal long arm of the X chromosome ( locus Xq11-Xq12). The protein coding region consists of about 2,757 nucleotides (919 codons ) spanning eight exons , labeled 1-8 or A-H. Introns vary in size from 0.7 to 26 kb . Like other nuclear receptors, the AR protein consists of several functional domains : the transactivation domain (also known as the transcription-regulation domain or the amino / NH2-terminal domain), the DNA-binding domain , the hinge region, and the steroid-binding domain (also referred to as the carboxyl-terminal ligand-binding domain). The transactivation domain is encoded by exon 1, constituting more than half of the AR protein. Exons 2 and 3 encode the DNA-binding domain, while the 5' part of exon 4 encodes the hinge region. The remaining portions of exons 4 through 8 encode the ligand binding domain. Trinucleotide Satellite Lengths and AR Transcriptional Activity The AR gene features two polymorphic trinucleotide microsatellites in exon 1. The first microsatellite, located nearest the 5' end, consists of 8 to 60 repetitions of the glutamine codon "CAG" and is referred to as the polyglutamine tract. The second microsatellite includes 4 to 31 repetitions of the glycine codon "GGC" and is known as the polyglycine tract. The average number of repetitions varies among ethnic groups, with Caucasians having an average of 21 CAG repeats and Blacks 18. In men, extreme lengths of the polyglutamine tract are linked to various diseases; fewer repetitions are associated with prostate cancer, hepatocellular carcinoma, and intellectual disability, while spinal and bulbar muscular atrophy (SBMA) is linked to 40 or more CAG repeats. Some research suggests an inverse relationship between the length of the polyglutamine tract and transcriptional activity in the AR protein, with longer tracts potentially linked to male infertility and undermasculinized genitalia. However, other studies have found no such correlation. A 2007 meta-analysis supports the correlation's existence, suggesting discrepancies can be resolved by considering sample size and study design. Some research also indicates that longer polyglycine tract lengths may be associated with genital masculinization defects in men, though other studies dispute this association. AR Mutations As of 2010, the AR mutation database has reported over 400 mutations, with the number continuing to rise. Inheritance is typically maternal and follows an X-linked recessive pattern; individuals with a 46,XY karyotype always express the mutant gene due to having only one X chromosome, while 46,XX carriers are minimally affected. Approximately 30% of AR mutations occur spontaneously and are not inherited. These de novo mutations result from a germ cell mutation or germ cell mosaicism in one of the parent's gonads, or a mutation in the fertilized egg itself. In one study, three out of eight de novo mutations occurred postzygotically, suggesting up to one-third result in somatic mosaicism. Not all AR gene mutations lead to androgen insensitivity; one specific mutation appears in 8 to 14% of genetic males but only affects a small number of individuals when other genetic factors are present. Other Causes Some individuals with CAIS or PAIS lack AR mutations despite having clinical, hormonal, and histological features that justify an AIS diagnosis; up to 5% of women with CAIS and 27 to 72% of individuals with PAIS do not have an AR mutation. In one patient, PAIS was attributed to a mutant steroidogenic factor-1 (SF-1) protein. In another case, CAIS resulted from a defect in transmitting a transactivating signal from the N-terminal region of the androgen receptor to the cell's basal transcription machinery. A coactivator protein interacting with the activation function 1 (AF-1) transactivation domain of the androgen receptor might have been deficient. The signal disruption could not be corrected by any known coactivators at the time, nor was the absent coactivator protein identified, leaving some experts skeptical that a mutant coactivator explains androgen resistance in CAIS or PAIS patients with a typical AR gene. XY karyotype Depending on the mutation, an individual with a 46,XY karyotype and AIS can exhibit a male (MAIS) or female (CAIS) phenotype, or may possess genitalia that are partially masculinized (PAIS). The gonads are testes regardless of phenotype due to the Y chromosome's influence. Therefore, a 46,XY female does not have ovaries and cannot contribute an egg for conception. In certain cases, 46,XY females develop a vestigial uterus and have been able to gestate children. Such instances are rare and have necessitated the use of an egg donor, hormone therapy, and IVF. Several case studies of fertile 46,XY males with AIS have been documented, although they are considered a minority. In some cases, infertile males with MAIS have managed to conceive children by increasing their sperm count through supplementary testosterone . A genetic male conceived by a man with AIS would not inherit his father's X chromosome , thus would neither inherit nor carry the gene for the syndrome. A genetic female conceived in this manner would receive her father's X chromosome and thus become a carrier . XX karyotype Genetic females (46,XX karyotype) possess two X chromosomes and thus have two AR genes. A mutation in one (but not both) results in a minimally affected, fertile female carrier. Some carriers have been observed to have slightly reduced body hair, delayed puberty, and/or tall stature, likely due to skewed X-inactivation. A female carrier will pass the affected AR gene to her children 50% of the time. If the affected child is a genetic female, she will also be a carrier. An affected 46,XY child will have AIS. A genetic female with mutations in both AR genes could theoretically arise from the union of a fertile man with AIS and a female carrier of the gene, or from a de novo mutation. However, given the rarity of fertile AIS men and the low incidence of AR mutation, the likelihood of this is small. The phenotype of such an individual remains speculative; as of 2010, no such documented case has been reported. Correlation of Genotype and Phenotype Individuals with partial AIS, as opposed to those with complete or mild forms, are born with ambiguous genitalia , making the decision to raise the child as male or female not straightforward. Unfortunately, precise knowledge of the AR mutation offers little insight into the phenotype ; the same AR mutation can lead to significant variation in masculinization levels among different individuals, even within the same family. The exact reasons for this variation are not fully understood, but potential factors include the lengths of polyglutamine and polyglycine tracts, sensitivity to and variations in the intrauterine endocrine environment, the impact of coregulatory proteins active in Sertoli cells , somatic mosaicism, expression of the 5RD2 gene in genital skin fibroblasts , and reduced AR transcription and translation from factors other than AR coding region mutations, an unidentified coactivator protein, enzyme deficiencies such as 21-hydroxylase deficiency , or other genetic variations like a mutant steroidogenic factor-1 protein. The extent of this variation is not uniform across all AR mutations and is more pronounced in some cases. Missense mutations that lead to a single amino acid change are known to produce the greatest phenotypic diversity. Pathophysiology Androgens and the Androgen Receptor The effects of androgens on the human body ( virilization , masculinization, anabolism , etc.) are not directly caused by androgens themselves but occur when androgens bind to androgen receptors; the androgen receptor mediates these effects in the human body. Similarly, the androgen receptor is generally inactive in the cell until it binds with androgens. The following steps illustrate how androgens and the androgen receptor collaborate to produce androgenic effects: Androgen enters the cell. Only specific organs in the body, like the gonads and the adrenal glands , produce the androgen testosterone . Testosterone is transformed into dihydrotestosterone , a chemically similar androgen, in cells that contain the enzyme 5-alpha reductase . Both androgens exert their effects by binding with the androgen receptor. Androgen binds with the androgen receptor. The androgen receptor is present throughout the tissues of the human body. Before binding with an androgen, the androgen receptor is attached to heat shock proteins . These heat shock proteins are released when androgen binds. Androgen binding prompts a stabilizing, conformational change in the androgen receptor. The two zinc fingers of the DNA-binding domain become exposed due to this new conformation. AR stability is believed to be supported by type II coregulators , which influence protein folding and androgen binding, or aid NH2/carboxyl-terminal interaction. The hormone-activated androgen receptor is phosphorylated . Receptor phosphorylation can occur prior to androgen binding, though the presence of androgen encourages hyperphosphorylation. The biological implications of receptor phosphorylation remain unknown. The hormone-activated androgen receptor translocates to the nucleus. Nucleocytoplasmic transport is partly facilitated by an amino acid sequence on the AR known as the nuclear localization signal . The AR's nuclear localization signal is mainly encoded in the hinge region of the AR gene. Homodimerization occurs. Dimerization is mediated by the second (nearest the 3' end) zinc finger . DNA binding to regulatory androgen response elements occurs. Target genes contain (or are flanked by) transcriptional enhancer nucleotide sequences that interact with the first zinc finger. These regions are referred to as androgen response elements. Coactivators are recruited by the AR. Type I coactivators (i.e., coregulators) are believed to affect AR transcriptional activity by facilitating DNA occupancy, chromatin remodeling , or the recruitment of general transcription factors associated with RNA polymerase II holocomplex. Target gene transcription follows. Thus, androgens bound to androgen receptors regulate the expression of target genes, thereby producing androgenic effects. In theory, some mutant androgen receptors can operate without androgens; in vitro research has shown that a mutant androgen receptor protein can trigger transcription without androgen if its steroid binding domain is removed. On the other hand, the steroid-binding domain might suppress the AR transactivation domain, possibly due to the AR's unliganded conformation. Androgens in fetal development Human embryos develop in a similar manner for the first six weeks, irrespective of genetic sex (46,XX or 46,XY karyotype); the only way to distinguish between 46,XX or 46,XY embryos during this period is to identify Barr bodies or a Y chromosome. The gonads start as tissue bulges known as the genital ridges at the back of the abdominal cavity , near the midline. By the fifth week, the genital ridges differentiate into an outer cortex and an inner medulla , and are termed indifferent gonads . By the sixth week, the indifferent gonads begin to differentiate based on genetic sex. If the karyotype is 46,XY, testes form due to the influence of the Y chromosome 's SRY gene. This process does not require androgen presence or a functional androgen receptor. Until about the seventh week of development, the embryo has indifferent sex accessory ducts , which include two pairs of ducts: the Müllerian ducts and the Wolffian ducts . Sertoli cells within the testes release anti-Müllerian hormone at this stage to inhibit the development of the Müllerian ducts, causing their degeneration. Without this anti-Müllerian hormone, the Müllerian ducts develop into the female internal genitalia ( uterus , cervix , fallopian tubes , and upper vaginal barrel ). Unlike the Müllerian ducts, the Wolffian ducts do not develop by default. In the presence of testosterone and functional androgen receptors, the Wolffian ducts transform into the epididymides , vasa deferentia , and seminal vesicles . If the testes do not secrete testosterone, or if the androgen receptors are not functional, the Wolffian ducts degenerate. Masculinization of the male external genitalia (the penis , penile urethra , and scrotum ), as well as the prostate , relies on the androgen dihydrotestosterone . Testosterone is converted into dihydrotestosterone by the 5-alpha reductase enzyme. If this enzyme is missing or deficient, dihydrotestosterone is not produced, and the external male genitalia do not develop properly. As is the case with the internal male genitalia , a functional androgen receptor is required for dihydrotestosterone to regulate the transcription of target genes involved in development. Pathogenesis of AIS Mutations in the androgen receptor gene can disrupt any stage of androgenization, from the synthesis of the androgen receptor protein to the transcriptional capability of the dimerized androgen-AR complex. AIS can occur if any of these steps are significantly impaired, as each is crucial for androgens to activate the AR and regulate gene expression . The specific steps affected by a mutation can often be predicted by identifying the mutation's location within the AR. This predictive ability is mainly retrospective, as the various functional domains of the AR gene have been understood through the analysis of specific mutations in different AR regions. For instance, mutations in the steroid binding domain have been shown to affect androgen binding affinity or retention , mutations in the hinge region affect nuclear translocation , mutations in the DNA-binding domain impact dimerization and DNA binding, and mutations in the transactivation domain affect target gene transcription regulation. However, even knowing the affected functional domain doesn't make predicting the phenotypical outcomes of a mutation straightforward. Some mutations can negatively impact multiple functional domains. For example, a mutation in one domain might adversely affect another by altering domain interactions. A single mutation can influence all downstream functional domains if it results in a premature stop codon or framing error , leading to a completely unusable (or unsynthesizable) androgen receptor protein. The steroid binding domain is especially susceptible to premature stop codons or framing errors, as it is located at the gene's end, making its information more prone to truncation or misinterpretation compared to other domains. More complex relationships have been observed due to mutated AR ; some mutations linked to male phenotypes have been associated with male breast cancer , prostate cancer , or in cases of spinal and bulbar muscular atrophy , diseases of the central nervous system . The male breast cancer seen in some PAIS cases is caused by a mutation in the AR's DNA-binding domain. This mutation is believed to disrupt AR's interaction with target genes, enabling it to act on additional targets, possibly in collaboration with the estrogen receptor protein, leading to cancerous growth . The pathogenesis of spinal and bulbar muscular atrophy (SBMA) shows that even the mutant AR protein itself can cause pathology . The trinucleotide repeat expansion of the polyglutamine tract in the AR gene associated with SBMA leads to the production of a misfolded AR protein that the cell cannot proteolyze and properly disperse. These misfolded AR proteins accumulate in the cell's cytoplasm and nucleus . Over 30 to 50 years, these aggregates build up and have a cytotoxic effect, eventually leading to the neurodegenerative symptoms associated with SBMA. Diagnosis The phenotypes associated with androgen insensitivity are not exclusive to AIS, so diagnosing AIS requires careful exclusion of other possibilities. Clinical signs suggestive of AIS include a short vagina or underdeveloped genitalia, partial or complete regression of Müllerian structures, bilateral nondysplastic testes, and impaired spermatogenesis and/or virilization. Laboratory results show a 46,XY karyotype and normal or elevated postpubertal testosterone, luteinizing hormone , and estradiol levels. The androgen binding activity of genital skin fibroblasts is generally reduced, though exceptions exist. The conversion of testosterone to dihydrotestosterone might be impaired. AIS is confirmed if androgen receptor gene sequencing identifies a mutation, although not all AIS cases (especially PAIS) will show an AR mutation (see Other Causes ). Each AIS type (complete, partial, and mild) has its own set of differential diagnoses to consider. There are reports of individuals with both AIS and certain conditions listed here, such as Klinefelter syndrome or Turner syndrome with mosaicism. The differential list varies depending on the suspected form of AIS: Chromosomal anomalies : Klinefelter syndrome (47,XXY karyotype) Turner syndrome (45,XO karyotype) Mixed gonadal dysgenesis (45,XO/46,XY karyotype) Tetragametic chimerism (46,XX/46,XY karyotype) Androgen biosynthetic dysfunction in 46,XY individuals : Luteinizing hormone (LH) receptor mutations Smith–Lemli–Opitz syndrome (associated with intellectual disability) Lipoid congenital adrenal hyperplasia 3β-hydroxysteroid dehydrogenase 2 deficiency 17α-hydroxylase deficiency 17,20 lyase deficiency 17β-hydroxysteroid dehydrogenase deficiency 5α-reductase deficiency Androgen excess in 46,XX individuals: 21-hydroxylase deficiency 3β-hydroxysteroid dehydrogenase 2 deficiency Cytochrome P450 oxidoreductase deficiency (disorder in mother causes 46,XX fetal virilization) 11β-hydroxylase deficiency Aromatase deficiency Glucocorticoid receptor mutations Maternal virilizing tumor (e.g. luteoma ) Increased androgen exposure in utero, not otherwise specified (e.g. androgenic drugs ) Developmental Mayer–Rokitansky–Küster–Hauser syndrome (46,XX karyotype) Swyer syndrome (46,XY karyotype) XX gonadal dysgenesis (46,XX karyotype) Leydig cell agenesis or hypoplasia , not otherwise specified (46,XY karyotype) Absent (vanishing) testes syndrome Ovotesticular DSD Testicular DSD (i.e. 46,XX sex reversal ) Teratogenic causes (e.g. estrogens , antiestrogens ) Other causes: Frasier syndrome (associated with progressive glomerulopathy) Denys–Drash syndrome (associated with nephropathy and Wilms tumor) WAGR syndrome (associated with Wilms tumor and aniridia) McKusick–Kaufman syndrome (associated with postaxial polydactyly) Robinow syndrome (associated with dwarfism) Aarskog–Scott syndrome (associated with facial anomalies) Hand-foot-genital syndrome (associated with limb malformations) Popliteal pterygium syndrome (associated with extensive webbing behind knees) Kallmann syndrome (often associated with anosmia) Hypospadias not otherwise specified Cryptorchidism not otherwise specified vaginal atresia not otherwise specified Management The management of AIS is currently restricted to symptomatic treatment ; there is no available method to rectify the defective androgen receptor proteins caused by AR gene mutations. Management areas include sex assignment , genitoplasty , gonadectomy concerning tumor risk, hormone replacement therapy , genetic couns eling , and psychological counseling .

Androgen deficiency is a medical condition marked by inadequate androgenic activity in the body. It most often affects women and is also known as Female androgen insufficiency syndrome (FAIS), although it can occur in both genders. Androgenic activity is facilitated by androgens (a group of steroid hormones with different affinities for the androgen receptor) and depends on factors like the abundance, sensitivity, and function of androgen receptors. Androgen deficiency is linked to symptoms such as lack of energy and motivation, depression, reduced desire (libido), and in severe cases, changes in secondary sex characteristics. Signs and symptoms In males, symptoms include loss of libido, impotence, infertility, shrinkage of the testicles, penis, and prostate, decreased masculinization (e.g., reduced facial and body hair growth), low muscle mass, anxiety, depression, fatigue, vasomotor symptoms (hot flashes), insomnia, headaches, cardiomyopathy and osteoporosis. Additionally, symptoms of hyperestrogenism, such as gynecomastia and feminization, may also be present in males. In males, a form of myopathy can arise from androgen deficiency, known as testosterone deficiency myopathy or (hypogonadotropic) hypogonadism with myopathy. Symptoms include elevated serum CK, symmetrical muscle wasting and muscle weakness (mainly proximal), a burning sensation in the feet at night, waddling gait, and impaired fasting glucose. EMG showed low volitional contraction of short duration polyphasic units. Muscle biopsy revealed signs of myonecrosis and regeneration, some fibre splitting, chronic inflammatory cells (macrophages) infiltrating degenerating fibres, and increased adipose and fibrous tissue (fibrosis). A predominance of type I (slow-twitch/oxidative) muscle fibres was observed, with some mixed atrophy of type II (fast-twitch/glycolytic) muscle fibres. Treatment involves hormone replacement therapy with testosterone. In females, hypoandrogenism includes loss of libido, reduced body hair growth, depression, fatigue, vaginal vasocongestion (which may cause cramps), vasomotor symptoms (e.g., hot flashes and palpitations), insomnia, headaches, osteoporosis, and reduced muscle mass. Since estrogens are synthesized from androgens, symptoms of hypoestrogenism may appear in both sexes in cases of severe androgen deficiency. Causes Hypoandrogenism is primarily due to dysfunction, failure, or absence of the gonads ( hypergonadotropic ) or impairment of the hypothalamus or pituitary gland ( hypogonadotropic ). This can result from a variety of causes, including genetic conditions (e.g., GnRH/gonadotropin insensitivity and enzymatic defects of steroidogenesis), tumors, trauma, surgery, autoimmunity, radiation, infections, toxins, drugs, and others. It may also result from conditions such as androgen insensitivity syndrome or hyperestrogenism. Old age may also contribute to hypoandrogenism, as androgen levels decrease with age. Diagnosis Diagnosis of androgen deficiency in males is based on symptoms along with at least two testosterone measurements taken in the morning after fasting. Testing is generally not recommended for asymptomatic individuals. Androgen deficiency is not typically evaluated for diagnosis in healthy women. Treatment Treatment may involve hormone replacement therapy with androgens for those with symptoms. Treatment primarily enhances sexual function in males. Gonadotropin-releasing hormone (GnRH)/GnRH agonists or gonadotropins may be administered in cases of hypogonadotropic hypoandrogenism. In 2015, the Food and Drug Administration (FDA) stated that neither the benefits nor the safety of testosterone have been confirmed for low testosterone levels due to aging. The FDA has required that testosterone product labels include warnings about the potential increased risk of heart attacks and strokes.

Ablepharon macrostomia syndrome ( AMS ) is an extremely rare autosomal dominant genetic disorder marked by unusual phenotypic features that predominantly affect the head, face, skull, skin, fingers, and genitals. AMS typically leads to abnormal ectoderm-derived structures. The most notable abnormalities include underdevelopment (microblepharon) or absence of eyelids, indicating the ablepharon aspect of the condition, and a wide, fish-like mouth, known as macrostomia. Recently, researchers and surgeons have questioned the term "Ablepharon" due to new findings and histological evidence showing some eyelid tissue is consistently present. Infants with AMS may also exhibit malformations of the abdominal wall and nipples. Children with AMS might face challenges with learning development, language difficulties, and intellectual disabilities. AMS results from mutations in the TWIST2 gene, among others, and shares phenotypic abnormalities with Barber–Say syndrome. Signs and symptoms AMS is generally marked by unusual appearances of the skin, eyes, fingers, genitals, head, and face. Infants with AMS may have thin, redundantly wrinkled skin and excessive facial creases; wide-set eyes with missing or severely underdeveloped eyelids and down-turned lower eyelids; and a wide, fish-like mouth that might be fused at the corners. Other facial and head features include a broad nasal bridge, wide, flared nostrils, and thick, flared alae nasi (edges of the nostrils). Abnormalities are also evident in the hands and fingers, as infants with AMS may have webbed fingers with limited flexibility. They may also have small, rudimentary ears set atypically low on the skull. The absence of the zygomatic bone is possible. The skin may be dry and coarse, excessively wrinkled around the face, loose around the hands, but tight around the finger joints, leading to reduced finger function. Causes Similar to Barber–Say syndrome, AMS is caused by mutations in the TWIST2 gene affecting a highly conserved residue of TWIST2 (twist-related protein 2). TWIST2 is a basic helix-loop-helix transcription factor that binds to E-box DNA motifs (5'-CANNTG-3') as a heterodimer and inhibits transcriptional activation. TWIST2 regulates mesenchymal stem cell differentiation and prevents premature or ectopic osteoblast differentiation. Mutations in TWIST2 that disturb these functions by altering DNA-binding activity could explain many AMS phenotypes. Current research highlights the substitution of the wild-type amino acid for Lysine at TWIST2 residue 75 as a key genetic cause of AMS. AMS is inherited in an autosomal dominant pattern, where an affected individual needs only one copy of the mutant allele to express the disease. Mechanism The mesenchyme is a mesodermal embryonic tissue capable of developing into various tissues based on the embryo's needs. It can develop into blood, cartilage, and membranes. In a typical patient, TWIST2 is highly expressed during embryonic development, especially in craniofacial development and chondrogenisis. TWIST2 prevents premature maturation of chondrogenic cells and osteoblasts, which form cartilage and bone, respectively. The dominant mutation in TWIST2 causes chondrogenic and osteoblastic cells to mature prematurely, leading to the primary craniofacial deformities seen in AMS patients. Diagnosis Ablepharon macrostomia syndrome can be diagnosed at birth through identification of characteristic physical findings, clinical evaluation, and specialized imaging techniques such as CT scans. Treatment Primary treatment focuses on alleviating immediate symptoms, such as using eye lubrication to relieve pain and dryness; antibiotics may also be prescribed to prevent infections and inflammation. Surgical measures can be taken, and a plastic surgeon can correct the lack of eyelids through reconstructive surgery. Eyelid surgery is considered a surgical emergency during the neonatal period, as eyelids are crucial for lubricating and protecting the cornea and maintaining optimal visual and facial aesthetics. Current eyelid reconstruction approaches involve recessing the levator aponeurosis, widening the shortened septum seen in these patients' eyelids, and descending the lid margin over the fissure before using subsequent skin grafts. Surgery to correct malformations of the mouth, ears, genitals, fingers, and skin can also be performed as needed. A maxillofacial surgeon can correct macrostomia, the wide, fish-like mouth. Skin treatments include creams to alleviate dryness and coarseness; in some cases, botulinum toxin and skin grafts have been used to improve overall appearance. It is highly recommended that patients seek help from pediatric psychologists throughout the treatment process. Prognosis While AMS has no cure, treatment plans from doctors can enhance development, overall quality of life, and physical appearance. Physical appearance cannot be fully corrected to the "norm," but the life expectancy of AMS patients is normal.

Aarskog–Scott syndrome ( AAS ) is a rare disorder inherited in an X-linked manner and is marked by short stature, facial abnormalities, and skeletal and genital anomalies. This condition primarily affects males, though females may exhibit mild features of the syndrome. Signs and symptoms Individuals with Aarskog–Scott syndrome often display distinctive facial features, such as widely spaced eyes (hypertelorism), a small nose, an elongated area between the nose and mouth (philtrum), and a widow's peak hairline. They often experience mild to moderate short stature during childhood, but their growth typically aligns with their peers during puberty. Common hand abnormalities in this syndrome include short fingers (brachydactyly), curved pinky fingers (fifth finger clinodactyly), webbing of the skin between some fingers (cutaneous syndactyly), and a single crease across the palm. Other abnormalities include heart defects and a split in the upper lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate). Most males with Aarskog–Scott syndrome have a shawl scrotum, where the scrotum surrounds the penis rather than hanging below. Occasionally, they may have undescended testes (cryptorchidism) or a soft out-pouching around the belly-button (umbilical hernia) or in the lower abdomen (inguinal hernia). The intellectual development of individuals with Aarskog–Scott syndrome varies significantly. Some may experience mild learning and behavioral challenges, while others have normal intelligence. In rare instances, severe intellectual disability has been noted. Genetics Mutations in the FGD1 gene are the sole known genetic cause of Aarskog-Scott syndrome. The FGD1 gene provides instructions for producing a protein that activates another protein called CDC42, which relays signals vital for various developmental processes before and after birth. Mutations in the FGD1 gene result in a malfunctioning protein. These mutations disrupt CDC42 signaling, leading to the diverse abnormalities seen in individuals with Aarskog-Scott syndrome. Approximately 20 percent of individuals with this disorder have identifiable mutations in the FGD1 gene. The cause of Aarskog-Scott syndrome in other affected individuals remains unknown. Diagnosis Genetic testing may be available for mutations in the FGDY1 gene. Genetic counseling is recommended for individuals or families who may carry this condition, as there are overlapping features with fetal alcohol syndrome. Additional examinations or tests can assist with diagnosis. These may include: comprehensive family history performing a detailed physical examination to document morphological features testing for genetic defects in FGDY1 x-rays to identify skeletal abnormalities echocardiogram to screen for heart abnormalities CT scan of the brain for cystic development X-ray of the teeth Ultrasound of the abdomen to identify undescended testes Treatment Like all genetic disorders, Aarskog–Scott syndrome cannot be cured, but various treatments are available to enhance the quality of life. Surgery may be necessary to correct some anomalies, and orthodontic treatment may be employed to address certain facial abnormalities. Trials of growth hormone have been effective in treating short stature associated with this disorder. Prognosis Some individuals may experience some cognitive delays, but children with this condition often possess good social skills. Some males may face fertility issues.

TS 45,X/46,XY mosaicism , also referred to as X0/XY mosaicism and mixed gonadal dysgenesis , is a variation in human sex development linked to sex chromosome aneuploidy and mosaicism of the Y chromosome. This condition is relatively rare at birth, with an incidence rate of approximately 1 in 15,000 live births. Mosaic loss of the Y chromosome in men who were previously non-mosaic becomes more common with age. The clinical presentations are highly variable, ranging from partial virilisation and ambiguous genitalia at birth, to individuals with completely male or female gonads. Most people with this karyotype appear to have normal male genitalia, while a minority have female genitalia, with many showing genital abnormalities or mixed sex traits. Individuals with X0/XY mosaicism also tend to have a higher number of other developmental anomalies. Psychomotor development remains normal. Signs and symptoms Conditions can be identified histologically and through karyotyping. The visible traits (phenotype) of this condition are quite variable, ranging from gonadal dysgenesis in males to Turner-like females and phenotypically normal males. The phenotypical expression can be ambiguous, male, or female, irrespective of the extent of the mosaicism. The most typical presentation of the 45,X/46,XY karyotype is a phenotypically normal male, with genital ambiguity being the next most common. There is a spectrum of chromosomal anomalies within 45,X/46,XY, where variations are intricate, and the actual outcome in individuals is often complex. Most patients with this karyotype exhibit abnormal gonadal histology and heights significantly below their genetic potential. Elevated gonadotropin levels have been noted in both male and female patients, along with low testosterone levels in male patients. Loss of the SHOX gene dosage is often linked to short stature. Psychomotor development is normal. As the gonads may be asymmetrical, the development of the Müllerian duct and Wolffian duct may also be asymmetrical. Due to the presence of dysgenetic gonadal tissue and Y chromosome material, there is a high risk of developing a gonadoblastoma. Causes Normally, all cells in an individual have 46 chromosomes, with one being an X and one a Y, or two Xs. However, sometimes during early DNA replication and cell division, one chromosome may be lost. In 45,X/46,XY, most or all of the Y chromosome is lost in one of the newly formed cells. All cells derived from this cell will lack the Y chromosome. Cells derived from those that retain the Y chromosome will be XY. The 46,XY cells will continue to multiply alongside the 45,X cells. The embryo, fetus, and eventually the baby will have a 45,X/46,XY constitution. Various chromosomal variations can lead to the 45,X/46,XY karyotype, including malformation (isodicentricism) of Y chromosomes, deletions, or translocations of Y chromosome segments. Such Y chromosome rearrangements can result in partial expression of the SRY gene, potentially causing abnormal genitals and testosterone levels. Diagnosis Identifying the 45,X/46,XY karyotype has significant clinical implications due to its effects on growth, hormonal balance, gonadal development, and histology. 45,X/46,XY is diagnosed by analyzing the chromosomes in a blood sample. The age of diagnosis varies based on the disease manifestations prompting cytogenetic testing. Many patients are diagnosed prenatally due to fetal factors (such as increased nuchal fold or abnormal serum levels), maternal age, or abnormal ultrasounds, while others are diagnosed postnatally due to external genital malformation. It is not uncommon for diagnosis to occur later in life due to short stature, delayed puberty, or both. 45,X/46,XY mosaicism can be detected prenatally through amniocentesis, but the proportion of 45,X cells in the amniotic fluid cannot reliably predict phenotypic outcomes, often complicating prenatal genetic counseling. Management The management of individuals with 45,X/46,XY mosaicism involves a multidisciplinary approach tailored to the specific needs and health concerns of the patient. Below are key aspects of the medical management: 1. Diagnosis and Genetic Counseling Karyotyping: Confirm the diagnosis through chromosomal analysis. - Genetic Counseling: Provide support and information about the condition, inheritance patterns, and implications for family planning. 2. Hormonal Therapy Estrogen Replacement Therapy: Typically initiated during puberty to promote secondary sexual characteristics in those with a more female phenotype. - Testosterone Therapy: May be considered for individuals with a more male phenotype or those who identify as male. 3. Monitoring and Management of Associated Conditions Cardiac Evaluation: Screening for congenital heart defects, which are more common in individuals with Turner syndrome. - Renal Ultrasound: Assess for kidney abnormalities, as these can be associated with the condition. - Thyroid Function Tests: Monitor for thyroid dysfunction, which can occur in this population. 4. Fertility Considerations Fertility Assessment: Discuss options for fertility preservation and assisted reproductive technologies if desired. - Surgical Options: Explore surgical interventions for individuals with testicular tissue to reduce the risk of gonadal tumors. 5. Psychological Support Mental Health Services: Provide access to counseling and support groups to address psychosocial issues related to gender identity, self-esteem, and social integration. 6. Regular Follow-Up Endocrinology: Regular follow-ups with an endocrinologist for hormone management. Pediatric and Adult Care: Transition from pediatric to adult care services, ensuring continuity in management. 7. Education and Advocacy Patient Education: Inform patients and families about the condition, potential health issues, and management strategies. - Advocacy: Encourage involvement in support networks and advocacy groups for individuals with intersex variations or Turner syndrome. By addressing these areas, healthcare providers can help individuals with 45,X/46,XY mosaicism lead healthy and fulfilling lives.

17β-Hydroxysteroid dehydrogenase III deficiency is a rare autosomal recessive disorder of sexual development that leads to 46,XY disorder of sex development (46,XY DSD). The reduced testosterone production by 17β-hydroxysteroid dehydrogenase III (17β-HSD III) results in atypical genitalia in affected males. Signs and symptoms 17-β-Hydroxysteroid dehydrogenase III deficiency causes 46,XY disorder of sex development (46,XY DSD) in males, with varying impacts on genitalia that may appear completely or mostly female, often with a blind vaginal pouch. Testes are typically located in the inguinal canal or within a bifid scrotum. Wolffian structures such as the epididymides, vas deferens, seminal vesicles, and ejaculatory ducts are present. This autosomal recessive deficiency is due to homozygous or compound heterozygous mutations in the HSD17B3 gene, which encodes the 17β-hydroxysteroid dehydrogenase III enzyme, disrupting the conversion of 17-keto to 17-hydroxysteroids. This enzyme plays a role in the final stage of steroidogenesis, converting androstenedione to testosterone and estrone to estradiol. Virilization of affected males still occurs at puberty. Genetics 17β-Hydroxysteroid dehydrogenase III deficiency is caused by mutations in the 17β-HSD III (17BHSD3) gene. It is an autosomal recessive disorder. Mechanism Androstenedione is produced in the testis and the adrenal cortex. It is synthesized from dehydroepiandrosterone (DHEA) or 17-hydroxyprogesterone. A deficiency in the HSD17B3 gene is biochemically characterized by reduced testosterone levels, leading to inadequate dihydrotestosterone formation during fetal development. At puberty, there is an increase in plasma luteinizing hormone and testicular secretion of androstenedione, causing a clinically significant higher ratio of androstenedione to testosterone. Diagnosis For diagnosing 17β-hydroxysteroid dehydrogenase III deficiency, consider the following: Increased androstenedione:testosterone ratio Thyroid dyshormonogenesis Genetic testing

Pueraria mirifica , also referred to as กวาวเครือ Kwao Krua (among other names), is a plant native to northern and northeastern Thailand and Myanmar. In Thailand, this plant is called "Kwao Krua Kao," where 'Kao' signifies white, setting Pueraria mirifica apart from other tuberous-rooted plants sharing the 'Kwao Krua' name, such as Butea superba , commonly known as Kwao Krua Deng (Red), along with the 'black' and 'dull grey' Kwao Krua varieties. The species was officially identified as Pueraria mirifica in 1952. When dried and powdered, the tuberous root of Pueraria mirifica has been traditionally consumed in Thailand as a rejuvenating herb to enhance youthfulness in both women and men. It is widely used in the now government-regulated practice of traditional Thai medicine. Benefits To use the tuberous root of Pueraria with large leaves, it is pounded and mixed with cow's milk. This medicine is believed to enhance memory, improve eloquence, enable memorization of three books of astrology, make the skin smooth like that of a six-year-old, extend life beyond 1,000 years, and prevent parasite-related diseases. Modern understanding of Pueraria mirifica can be traced back to a booklet referencing its ancient use, where the author Luang Anusan Suntara claimed it reduced wrinkles, eliminated gray hair, improved eyesight and memory, among other benefits. Uses Various herbal supplements assert that extracts of Pueraria mirifica offer health benefits such as increasing breast size, enhancing skin, nail, and hair health, reducing acne, balancing hormones, and providing other rejuvenating effects. Chemical Constituents Pueraria mirifica contains several Phytoestrogens including Deoxymiroestrol, Daidzin, Daidzein, Genistin, Genistein, Coumestrol, Kwakhurin, and Mirificine, along with β-sitosterol, Stigmasterol, Campesterol, and Mirificoumestan. There is conflicting evidence regarding the presence of miroestrol. It also contains the Cytotoxic non-phytoestrogen Spinasterol.

Cortisol is a steroid hormone in the glucocorticoid class and is also a stress hormone. When used as medication, it is referred to as hydrocortisone. Cortisol is produced in many animals, primarily by the zona fasciculata of the adrenal cortex in an adrenal gland. In other tissues, its production is lower. Cortisol is released in a diurnal cycle and increases in response to stress and low blood-glucose concentration. Its functions include raising blood sugar through gluconeogenesis, suppressing the immune system, aiding in metabolism, and reducing bone formation. These actions occur when cortisol binds to glucocorticoid or mineralocorticoid receptors within a cell, affecting gene expression by binding to DNA. Health effects Metabolic response Metabolism of glucose Cortisol is crucial in regulating glucose metabolism, promoting gluconeogenesis (glucose synthesis) and glycogenesis (glycogen synthesis) in the liver, and glycogenolysis (breakdown of glycogen) in skeletal muscle. It raises blood glucose levels by reducing glucose uptake in muscle and adipose tissue, decreasing protein synthesis, and increasing lipolysis. These processes collectively elevate blood glucose levels, fueling the brain and other tissues during the fight-or-flight response. Cortisol also releases amino acids from muscle, aiding gluconeogenesis. Its effects are complex and varied. Overall, cortisol stimulates gluconeogenesis (the synthesis of 'new' glucose from non-carbohydrate sources, mainly in the liver, but also in the kidneys and small intestine under certain conditions). This results in increased blood glucose levels, further supported by decreased sensitivity of peripheral tissue to insulin, preventing glucose uptake from the blood. Cortisol allows hormones like glucagon and adrenaline to increase glucose production. Cortisol indirectly influences liver and muscle glycogenolysis (breaking down glycogen to glucose-1-phosphate and glucose) through glucagon and adrenaline. It also facilitates glycogen phosphorylase activation, necessary for adrenaline's effect on glycogenolysis. Interestingly, cortisol promotes both gluconeogenesis (biosynthesis of glucose) in the liver and glycogenesis (polymerization of glucose into glycogen), thus stimulating glucose/glycogen turnover in the liver. In contrast, in skeletal muscle, cortisol promotes glycogenolysis (breakdown of glycogen into glucose) indirectly through catecholamines, working with them to break down muscle glycogen into glucose for muscle use. Metabolism of proteins and lipids Prolonged elevated cortisol levels can lead to proteolysis (protein breakdown) and muscle wasting, providing substrates for gluconeogenesis. Cortisol's effects on lipid metabolism are complex; while chronic high cortisol levels lead to lipogenesis, an acute increase promotes lipolysis. This discrepancy is explained by cortisol-induced high blood glucose stimulating insulin release, which promotes lipogenesis over time. Immune response Cortisol inhibits the release of substances causing inflammation and treats conditions from overactive B-cell antibody responses, like inflammatory and rheumatoid diseases, and allergies. Low-dose topical hydrocortisone, available over-the-counter in some countries, treats skin issues like rashes and eczema. Cortisol suppresses interleukin 12 (IL-12), interferon gamma (IFN-gamma), IFN-alpha, and tumor necrosis factor alpha (TNF-alpha) production by antigen-presenting cells (APCs) and T helper cells (Th1 cells), while upregulating interleukin 4, interleukin 10, and interleukin 13 by Th2 cells, shifting towards a Th2 immune response. This shift during infection is protective, preventing excessive inflammation. Cortisol weakens the immune system by preventing T-cell proliferation, making interleukin-2 producing T-cells unresponsive to interleukin-1 and unable to produce IL-2. Cortisol downregulates the IL-2R receptor on helper T-cells, favoring a Th2 immune response and B-cell antibody production. Cortisol negatively feeds back on IL-1. An immune stressor causes peripheral immune cells to release IL-1 and other cytokines like IL-6 and TNF-alpha, stimulating the hypothalamus to release corticotropin-releasing hormone (CRH), which stimulates adrenocorticotropic hormone (ACTH) production in the adrenal gland, increasing cortisol production. Cortisol then inhibits TNF-alpha production and reduces immune cell responsiveness to IL-1. This system regulates the immune response to the correct level, like a thermostat. However, in severe infections or when the immune system is overly sensitized, the correct set point may not be reached. Due to cortisol and other signaling molecules downregulating Th1 immunity, certain infections (like Mycobacterium tuberculosis) can trigger an incorrect immune response. Lymphocytes, including B-cell lymphocytes, are key agents of humoral immunity. Increased lymphocytes in lymph nodes, bone marrow, and skin enhance the humoral immune response, releasing antibodies that neutralize pathogens, promote opsonization, and activate complement pathways. Antibodies neutralize pathogens, target them for destruction, and activate complement molecules to enhance immune response. Rapid administration of corticosterone or RU28362 in adrenalectomized animals changes leukocyte distribution. Natural killer cells target larger threats like bacteria and tumors. Cortisol reduces their effectiveness by downregulating cytotoxicity receptors, while prolactin has the opposite effect, enhancing receptor expression and function. Cortisol stimulates copper enzymes, including lysyl oxidase for collagen and elastin cross-linking, and superoxide dismutase, which helps poison bacteria. Viruses like influenza and SARS-CoV suppress stress hormone secretion to evade immune responses. They produce a protein mimicking ACTH, leading to antibodies that suppress adrenal function and cortisol production, allowing immune evasion. This viral strategy can severely impact the host, as cortisol is crucial for metabolism, blood pressure, inflammation, and immune response regulation. A lack of cortisol can cause adrenal insufficiency, with symptoms like fatigue, weight loss, low blood pressure, nausea, and abdominal pain, impairing the host's stress and infection response. By suppressing cortisol, viruses can evade the immune system and weaken host health and resilience. Other effects Metabolism Glucose Cortisol opposes insulin, contributes to hyperglycemia by promoting gluconeogenesis, and reduces peripheral glucose utilization (insulin resistance) by decreasing the movement of glucose transporters (particularly GLUT4) to the cell membrane. It also enhances glycogen synthesis (glycogenesis) in the liver, storing glucose in an easily accessible form. Bone and collagen Cortisol decreases bone formation, promoting the long-term development of osteoporosis (a progressive bone disease). This occurs through two mechanisms: cortisol stimulates RANKL production by osteoblasts, activating osteoclasts via RANK receptors, and inhibits osteoprotegerin (OPG) production, which acts as a decoy receptor for RANKL. When RANKL binds to OPG, no response occurs, unlike binding to RANK, which activates osteoclasts. It transports potassium out of cells in exchange for an equal number of sodium ions. This can lead to hyperkalemia during metabolic shock post-surgery. Cortisol also decreases calcium absorption in the intestines and reduces collagen synthesis. Amino acid Cortisol increases free amino acids in the serum by inhibiting collagen formation, reducing amino acid uptake by muscles, and inhibiting protein synthesis. Cortisol (as opticortinol) may inversely suppress IgA precursor cells in the intestines of calves. It also inhibits IgA in serum, similar to IgM, but does not inhibit IgE. Electrolyte balance Cortisol enhances the glomerular filtration rate and renal plasma flow, increasing phosphate excretion, sodium and water retention, and potassium excretion by acting on mineralocorticoid receptors. It also increases sodium and water absorption and potassium excretion in the intestines. Sodium Cortisol facilitates sodium absorption in the small intestine of mammals. However, sodium depletion does not influence cortisol levels, so cortisol cannot regulate serum sodium. The original role of cortisol may have been sodium transport, supported by its function in freshwater and saltwater fish for sodium regulation. Potassium A sodium load enhances cortisol's promotion of potassium excretion. Corticosterone acts similarly to cortisol in this regard. For potassium to exit the cell, cortisol moves an equal number of sodium ions into the cell, easing pH regulation, unlike the typical potassium-deficient scenario where two sodium ions enter for every three potassium ions exiting, akin to the deoxycorticosterone effect. Stomach and kidneys Cortisol stimulates gastric acid production. Its only direct effect on kidney hydrogen-ion excretion is enhancing ammonium ion excretion by deactivating renal glutaminase. Memory Cortisol collaborates with adrenaline (epinephrine) to form memories of short-term emotional events, a proposed mechanism for storing flash bulb memories, possibly to remember what to avoid. However, prolonged cortisol exposure damages hippocampus cells, impairing learning. Diurnal cycles Diurnal cycles of cortisol levels occur in humans. Stress Prolonged stress can result in elevated levels of circulating cortisol (considered one of the key "stress hormones"). Effects during pregnancy In human pregnancy, increased fetal cortisol production between weeks 30 and 32 starts the production of fetal lung pulmonary surfactant to aid lung maturation. In fetal lambs, glucocorticoids (mainly cortisol) rise after about day 130, causing a significant increase in lung surfactant by around day 135. While lamb fetal cortisol is primarily of maternal origin during the first 122 days, by day 136, 88% or more is derived from the fetus. Although the timing of increased fetal cortisol in sheep can vary, it typically occurs about 11.8 days before labor begins. In various livestock species (e.g., cattle, sheep, goats, and pigs), a late gestation fetal cortisol surge initiates parturition by removing the progesterone block on cervical dilation and myometrial contraction. The mechanisms causing this effect on progesterone differ among species. In sheep, where the placenta produces sufficient progesterone to maintain pregnancy after about day 70, the prepartum fetal cortisol surge prompts the placental conversion of progesterone to estrogen. (The increased estrogen level stimulates prostaglandin secretion and oxytocin receptor development.) Fetal exposure to cortisol during gestation can lead to various developmental outcomes, including changes in prenatal and postnatal growth patterns. In marmosets, a New World primate species, pregnant females exhibit varying cortisol levels during gestation, both within and among individuals. Infants born to mothers with high gestational cortisol in the first trimester had lower growth rates in body mass indices compared to those born to mothers with low gestational cortisol (about 20% lower). However, these high-cortisol infants experienced faster postnatal growth rates than low-cortisol infants later in postnatal periods, achieving complete growth catch-up by 540 days of age. These findings suggest that gestational cortisol exposure has significant potential fetal programming effects on both pre and postnatal growth in primates. Cortisol face Elevated cortisol levels can cause facial swelling and bloating, resulting in a round and puffy appearance known as "cortisol face." Synthesis and release Cortisol is synthesized in the human body by the adrenal gland's zona fasciculata, the second of the three layers of the adrenal cortex. This cortex forms the outer "bark" of each adrenal gland, located atop the kidneys. Cortisol release is regulated by the hypothalamus in the brain. The hypothalamus secretes corticotropin-releasing hormone, prompting cells in the adjacent anterior pituitary to release adrenocorticotropic hormone (ACTH) into the bloodstream, which carries it to the adrenal cortex. ACTH stimulates the production of cortisol and other glucocorticoids, the mineralocorticoid aldosterone, and dehydroepiandrosterone. Testing of individuals The normal values shown in the following tables apply to humans (normal levels vary among species). Measured cortisol levels, and thus reference ranges, depend on the sample type, analytical method used, and factors such as age and sex. Therefore, test results should always be interpreted using the reference range from the laboratory that provided the result. An individual's cortisol levels can be measured in blood, serum, urine, saliva, and sweat. Reference ranges for blood plasma content of free cortisol Time Lower limit Upper limit Unit 09:00 am 140 700 nmol/L 5 25 μg/dL Midnight 80 350 nmol/L 2.9 13 μg/dL With a molecular weight of 362.460 g/mole, the conversion factor from μg/dL to nmol/L is roughly 27.6; therefore, 10 μg/dL is approximately 276 nmol/L. Reference ranges for urinalysis of free cortisol (urinary free cortisol or UFC) Lower limit Upper limit Unit 28 or 30 280 or 490 nmol /24h 10 or 11 100 or 176 μg /24 h Cortisol adheres to a circadian rhythm, making it ideal to measure cortisol levels four times daily using saliva tests for accuracy. An individual might have normal overall cortisol but experience lower levels at specific times and higher levels at others. This variability leads some experts to question the clinical value of cortisol measurement. Cortisol is lipophilic and is transported bound to transcortin (also known as corticosteroid-binding globulin (CBG)) and albumin. Only a small portion of total serum cortisol is unbound and biologically active. Cortisol binds to transcortin through hydrophobic interactions in a 1:1 ratio. Serum cortisol assays measure total cortisol, which can be misleading for patients with altered serum protein levels. The salivary cortisol test avoids this issue, as only free cortisol can cross the blood-saliva barrier. Transcortin particles are too large to traverse this barrier, which consists of epithelial cell layers in the oral mucosa and salivary glands. Cortisol can be incorporated into hair from blood, sweat, and sebum. A 3-centimeter segment of scalp hair can represent 3 months of growth, although growth rates vary across different scalp areas. Hair cortisol is a reliable marker of chronic cortisol exposure. Automated immunoassays lack specificity and exhibit significant cross-reactivity due to interactions with cortisol's structural analogs, resulting in differences across assays. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) enhances specificity and sensitivity. Disorders of cortisol production Certain medical conditions are associated with abnormal cortisol production, including: Primary hypercortisolism (Cushing's syndrome): excessive cortisol levels Secondary hypercortisolism (pituitary tumor leading to Cushing's disease, pseudo-Cushing's syndrome) Primary hypocortisolism (Addison's disease, Nelson's syndrome): insufficient cortisol levels Secondary hypocortisolism (pituitary tumor, Sheehan's syndrome) Regulation The primary regulation of cortisol is through the pituitary gland peptide, ACTH, which likely controls cortisol by managing calcium movement into cortisol-secreting target cells. ACTH is regulated by the hypothalamic peptide corticotropin-releasing hormone (CRH), which is under nervous control. CRH works synergistically with arginine vasopressin, angiotensin II, and epinephrine. (In swine, which do not produce arginine vasopressin, lysine vasopressin acts synergistically with CRH.) When activated macrophages secrete IL-1, which synergizes with CRH to increase ACTH, T-cells also release glucosteroid response modifying factor (GRMF) and IL-1; both increase the cortisol needed to inhibit nearly all immune cells. Immune cells then regulate themselves, but at a higher cortisol setpoint. In diarrheic calves, the cortisol increase is minimal compared to healthy calves and decreases over time. Due to interleukin-1's synergism with CRH, the cells retain some fight-or-flight override. Cortisol has a negative feedback effect on interleukin-1, which is especially useful for treating diseases that cause excessive CRH secretion, such as those from endotoxic bacteria. Suppressor immune cells are unaffected by GRMF, so the effective setpoint for immune cells might be higher than that for physiological processes. GRMF primarily affects the liver rather than the kidneys for some physiological processes. High-potassium media (which stimulates aldosterone secretion in vitro ) also stimulate cortisol secretion from the fasciculata zone of canine adrenals—unlike corticosterone, which potassium does not affect. Potassium loading also raises ACTH and cortisol in humans. This likely explains why potassium deficiency causes a decline in cortisol and decreases the conversion of 11-deoxycortisol to cortisol. This may also play a role in rheumatoid arthritis pain, as cell potassium is always low in RA. Ascorbic acid, especially in high doses, has been shown to mediate responses to psychological stress and accelerate the reduction of circulating cortisol levels post-stress. This is evidenced by decreased systolic and diastolic blood pressures and reduced salivary cortisol levels after ascorbic acid treatment. Factors increasing cortisol levels Viral infections raise cortisol levels through cytokine activation of the HPA axis. Intense (high VO2 max) or prolonged aerobic exercise temporarily increases cortisol levels to boost gluconeogenesis and maintain blood glucose; however, cortisol returns to normal after eating (restoring a neutral energy balance). Severe trauma or stressful events can elevate cortisol levels in the blood for extended periods. Low-carbohydrate diets cause a short-term increase in resting cortisol (≈3 weeks) and elevate the cortisol response to aerobic exercise in both the short and long term. An increase in ghrelin, the hunger-stimulating hormone, raises cortisol levels. Biochemistry Biosynthesis Cortisol is produced from cholesterol. This process occurs in the zona fasciculata of the adrenal cortex. The term "cortisol" originates from 'cortex', meaning "the outer layer", which refers to the adrenal cortex where cortisol is formed. In humans, the adrenal cortex also generates aldosterone in the zona glomerulosa and some sex hormones in the zona reticularis, but cortisol is its primary secretion in humans and many other species. In cattle, corticosterone levels can match or surpass cortisol levels. In humans, the adrenal gland's medulla, located beneath the cortex, primarily releases the catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine) during sympathetic activation. The production of cortisol in the adrenal gland is stimulated by the anterior lobe of the pituitary gland through ACTH, which is itself stimulated by CRH released by the hypothalamus. ACTH enhances cholesterol concentration in the inner mitochondrial membrane by regulating the steroidogenic acute regulatory protein. It also promotes the primary rate-limiting step in cortisol synthesis, converting cholesterol to pregnenolone, catalyzed by Cytochrome P450SCC (side-chain cleavage enzyme). Metabolism 11beta-hydroxysteroid dehydrogenases Cortisol is reversibly converted to cortisone by the 11-beta hydroxysteroid dehydrogenase system (11-beta HSD), which comprises two enzymes: 11-beta HSD1 and 11-beta HSD2. This conversion involves the oxidation of the hydroxyl group at the 11-beta position. A-ring reductases (5alpha- and 5beta-reductases) Cortisol is also irreversibly converted into 5-alpha tetrahydrocortisol (5-alpha THF) and 5-beta tetrahydrocortisol (5-beta THF), with 5-alpha reductase and 5-beta-reductase serving as the rate-limiting factors, respectively. 5-Beta reductase also limits the conversion of cortisone to tetrahydrocortisone. Cytochrome P450, family 3, subfamily A monooxygenases Cortisol is further metabolized irreversibly into 6β-hydroxycortisol by cytochrome p450-3A monooxygenases, primarily CYP3A4. Drugs that induce CYP3A4 can speed up cortisol clearance. Chemistry Cortisol is a naturally occurring pregnane corticosteroid and is also referred to as 11β,17α,21-trihydroxypregn-4-ene-3,20-dione .

5α-Reductase 2 deficiency (5αR2D) is an autosomal recessive disorder resulting from mutations that disrupt the function of SRD5A2 , a gene situated on chromosome 2 that encodes the enzyme 5α-reductase type 2 (5αR2). This enzyme is expressed in specific tissues and facilitates the conversion of testosterone (T) into 5α-dihydrotestosterone (DHT). DHT is crucial for sexual differentiation. This rare deficiency leads to atypical sex development in genetic males (individuals with a 46XY karyotype), showing a wide range of presentations, particularly in the genitalia. Many individuals with 5-alpha reductase deficiency are assigned female at birth based on their external genitalia. In other instances, affected infants are assigned male at birth due to external genitalia, often characterized by a small penis (micropenis) and a urethra opening on the underside of the penis (hypospadias). Some infants may be assigned either female or male at birth as their genitalia are ambiguous. During puberty, increased levels of male sex hormones lead to the development of secondary sex characteristics, such as increased muscle mass, a deeper voice, pubic hair growth, and a growth spurt. The penis and scrotum may enlarge. People with 5-alpha reductase deficiency typically do not develop much facial or body hair. Signs and symptoms Affected individuals show a variety of presentations, including atypical genitalia (ranging from female-like to underdeveloped male), hypospadias, and isolated micropenis. The internal reproductive structures (vasa deferentia, seminal vesicles, epididymides, and ejaculatory ducts) are normal, but testes are often undescended, and prostate hypoplasia is common. Males with identical mutations in SRD5A2 may have varying phenotypes, suggesting additional factors influencing clinical presentation. Although genetically female individuals (with two X chromosomes) may inherit variants in both copies of the SRD5A2 gene, their sexual development is unaffected. Female sex characteristics do not require DHT, so a lack of steroid 5-alpha reductase 2 activity does not cause physical changes in these individuals. Virilization of genitalia, voice deepening, and muscle mass development occur during puberty in affected individuals, and height is not affected. Gynecomastia is rare, and bone density remains normal, unlike in 46,XY DSD from other causes such as partial androgen insensitivity syndrome and 17β-hydroxysteroid dehydrogenase 3 deficiency. Facial and body hair is reduced, and male pattern baldness does not occur. Spontaneous fertility in individuals with 5αR2D is very rare (though documented) due to semen abnormalities, including reduced sperm counts, high semen viscosity, and sometimes a lack of primary spermatocytes. This indicates that DHT is important for spermatocyte differentiation. The wide range of presentations aligns with highly variable sperm counts among affected individuals. Testicular function may also be impaired by incomplete descent and the genetic mutation itself. Genetics Two distinct genes, each comprising five exons and four introns, named SRD5A1 and SDR5A2, encode two different 5α-reductases. The human 5α-reductase-2 gene (SRD5A2) is found on the short arm of chromosome 2 at band 23, encoding a 254 amino acid protein, known as 5α-reductase type 2. The 5α-reductase-1 gene (SRD5A1) is located in band 15 on the short arm of chromosome 5, encoding a 259 amino acid protein, called 5α-reductase type 1. The high amino acid sequence identity of their proteins (approximately 60%) suggests a common ancestral gene during evolution. However, the role of 5α-reductase type 1 is not well understood. Mutations in the SRD5A2 gene can lead to a 46,XY disorder of sex development (46,XY DSD) known as 5α-reductase-2 deficiency. These mutations are more prevalent in regions with specific ethnic backgrounds and high inbreeding coefficients. They produce proteins with varying degrees of enzymatic activity, from an unstable isoenzyme to complete loss of activity. Among the 254 amino acids in the 5α-reductase type 2 protein, mutations in codons specifying 67 different residues have been identified, with multiple mutations in several amino acid codons. The first identified SRD5A2 mutation was nearly a complete deletion discovered through analysis of affected individuals in a Papua New Guinean tribe. Most SRD5A2 mutations are missense mutations, but small deletions, splice junction mutations, and large deletions have also been observed. These mutations result in a range of effects from destabilizing 5αR2 to complete loss of activity. SRD5A2 mutations are inherited in an autosomal recessive manner. Homozygous defects are more frequent than compound heterozygous ones. For many common mutations, a phenotype-genotype correlation is not established, and individuals with the same 5αR2 mutations exhibit variable phenotypes, suggesting other genetic factors influence phenotype. Mechanism 5α-Reductase type 2 (5αR2) is an enzyme encoded by the SRD5A2 gene, expressed in specific tissues in the male body from fetal development to adulthood. It catalyzes the conversion of testosterone (T) into 5α-dihydrotestosterone (DHT) within cells. DHT is the most potent ligand for the androgen receptor (AR). Once bound, the DHT-AR complex moves from the cytoplasm to the nucleus, activating androgen receptor-regulated genes involved in processes such as male sexual differentiation. Diagnosis Diagnosis typically occurs between birth and puberty. Pseudovaginal perineoscrotal hypospadias with female-appearing genitalia and pubertal virilization is the classic syndrome linked to 5αR2D, but modern diagnostic techniques can identify the deficiency shortly after birth and recognize its broad spectrum of presentations. The initial diagnosis of 46,XY DSD is suggested by obvious genital abnormalities. Clinical evaluation for diagnosing 46,XY DSD with apparent female genitalia includes enlarged clitoris, posterior labial fusion, and inguinal/labial mass. For apparent male genitalia, it includes nonpalpable testes, micropenis, isolated perineal hypospadias, or mild hypospadias with undescended testis. Family and prenatal history are also considered. Karyotyping and SRY gene analysis on peripheral leukocytes exclude sex chromosome abnormalities. With an XY karyotype and normal SRY, 46,XY DSD is differentiated through endocrinological measurements of T/DHT ratios (indicating 5αR2 activity) and precise anatomical imaging, as 5αR2D can be difficult to distinguish from other 46,XY DSD causes (e.g., partial androgen insensitivity syndrome and 17β-hydroxysteroid dehydrogenase type 3 enzyme deficiencies). Measuring serum DHT concentration is challenging due to low concentrations and high cross-reactivity. High assay specificity is needed to measure DHT concentrations since serum T levels are generally 10 times higher than DHT in young males. Endocrinological tests for T/DHT ratios can be difficult to interpret as the normal ratio level varies with age and severity of 5αR2 activity impairment. Affected young males of at least pubertal age with normal serum T levels show elevated T/DHT levels (normal T, lower than normal DHT). Stimulation with human chorionic gonadotropin (hCG) (or testosterone enanthate) is needed in prepubertal children (with stimulation and samples taken over several days) to increase serum testosterone levels for measurement. Interpreting T/DHT ratios in male newborns is particularly challenging due to neonatal testosterone surge and higher than normal 5α-reductase type 1 activity. SRD5A2 gene analysis is recommended for newborn diagnosis. Generally, 5αR2D is diagnosed with T/DHT ratios over 18, with ratios over 30 seen in severely affected individuals. 5αR2D can also be indicated by low ratios of 5α- to 5β-reduced steroids, measured in urine via gas chromatography–mass spectrometry. Ultrasonography is the primary method for assessing internal reproductive organs for diagnosis, while genitography and voiding cystourethrography are used to resolve structures such as urethral and vaginal tracts. The use of pelvic MRI for diagnostic imaging for 5αR2D is still debated. Management One of the most challenging and controversial topics in 46,XY DSD is "sex assignment" or "sex of rearing". This is particularly true in 5αR2D, as most affected individuals have undervirilized genitalia at birth but virilize to varying degrees at puberty. Historically, most 5αR2D individuals have been "raised as females", but later reports show that over half of those experiencing virilizing puberty adopted a male gender identity, challenging historical practices. The aim of sex assignment/rearing is to maximize the likelihood of a concordant gender identity in adulthood. Factors influencing gender identity are complex and not easily reported, but include sex chromosomes, androgen exposure, psychosocial development, cultural expectations, family dynamics, and social circumstances. Female sex rearing in 5αR2D individuals involves surgical procedures like childhood gonadectomy (to prevent virilization at puberty) and vaginoplasty. Lifelong hormonal treatments are also needed for the development and maintenance of female secondary sex characteristics. Male sex of rearing avoids lifelong hormonal treatments and allows for potential fertility. Cryptorchidism and hypospadias must be addressed to prevent damage to the seminiferous tubules, which are essential for spermatogenesis and fertility. Some approaches advocate for diagnosis during infancy before any gender assignment or surgical interventions. The intersection of the child's well-being, parental wishes, recommendations of the medical team, and local laws makes decision-making challenging in these cases. The necessity and ethics around consent and deception involved in administering such interventions have been seriously questioned. Assisted reproduction methods involving sperm extraction and concentration for intrauterine insemination, intracytoplasmic sperm injection, and in vitro fertilization have all shown successful fertility outcomes for those with 5αR2D.

Turner syndrome (TS) is a congenital condition (present from birth) that exclusively affects females. It occurs when one of the two X chromosomes is either partially or completely missing. Turner syndrome results in a range of features and symptoms, impacting each individual differently. However, short stature and reduced ovary function (primary ovarian insufficiency) are the two most prevalent characteristics. Turner syndrome affects 1 in 2,000 to 1 in 2,500 female infants. It is the most common condition related to sex chromosomes in newborn girls. Symptoms and Causes Humans generally have 23 pairs of chromosomes (46 in total). These chromosomes are divided into 22 numbered pairs (autosomes) and one pair of sex chromosomes. Each biological parent contributes one chromosome to form a pair. The 23rd pair typically consists of one X and one Y chromosome in males and two X chromosomes in females. Turner syndrome occurs when one of a baby’s two X chromosomes is missing or incomplete. Researchers have yet to determine why this happens. Types of Turner syndrome Turner syndrome (TS) can vary based on how one of the X chromosomes is affected: Monosomy X : In this type, each cell contains only one X chromosome instead of two. Approximately 45% of individuals with TS have monosomy X. This chromosomal anomaly occurs randomly during the formation of reproductive cells (eggs or sperm) in the biological parent of the affected person. If one of these atypical reproductive cells contributes to the genetic composition of a fetus during conception, the baby will be born with a single X chromosome in each cell. Mosaic Turner syndrome : This type accounts for about 30% of TS cases. Some of your child’s cells have two X chromosomes, while others have only one. It occurs randomly during cell division early in pregnancy. Inherited Turner syndrome : In rare instances, babies may inherit TS, meaning their biological parent was born with it and passed it on. This type typically results from a missing part of the X chromosome. What are the symptoms of Turner syndrome? Turner syndrome manifests in various ways. It can lead to multiple characteristics or features, as well as certain health conditions, which can differ in severity. Depending on the type of TS, signs of the syndrome may be noticeable: Before birth. Shortly after birth. In early childhood. In early adolescence. In adulthood. Since TS affects everyone differently, you should consult your healthcare provider about what symptoms and features to expect or watch for based on your or your child’s unique genetic profile. Common features of Turner syndrome The primary feature of Turner syndrome is short stature. Nearly all individuals with TS: Grow more slowly than their peers during childhood and adolescence. Short stature typically becomes noticeable by age 5. Experience delayed puberty and lack of growth spurts, resulting in an average adult height of 4 feet, 8 inches. (If your child is diagnosed early, growth hormone therapy can increase their height by up to 5 inches, leading to an average adult height of 5’1”.) Another common feature is differences in sexual development. Most individuals with TS: Typically do not undergo puberty unless they receive hormone therapy in late childhood and early adolescence. May not experience breast development without hormone therapy. May not have menstrual periods (amenorrhea). Have smaller-than-expected ovaries that may only function for a few years or not at all (primary ovarian insufficiency or POI). Have low levels of sex hormones (such as estrogen). Experience infertility. In addition to short stature, individuals with Turner syndrome often exhibit certain physical characteristics, which may include: Unique ear features, such as low-set ears, elongated ears, cup-shaped ears, and thick ear lobes. A low hairline at the back of the neck. A small and receding lower jaw, potentially affecting tooth development and alignment. A short, broad neck or a webbed neck with extra skin folds. A broad chest. Arms that slightly angle outwards at the elbows (cubitus valgus). Absence of a knuckle in a specific finger or toe, making it shorter than the others. Flat feet (pes planus). Narrow fingernails and toenails. Numerous small colored spots (pigmented nevi) on the skin. Health conditions linked to Turner syndrome Individuals with Turner syndrome have an increased risk of certain health conditions, though not everyone with TS will experience them. Cardiovascular conditions Those with Turner syndrome may encounter heart and blood vessel issues, some of which can be severe. Up to 50% of individuals with TS are born with a congenital heart condition affecting the heart's structure. Cardiovascular issues may include: Bicuspid aortic valve. Coarctation of the aorta. Elongation of the aortic arch. High blood pressure (hypertension). Bone Conditions Bone conditions are frequently observed in TS and can include: Higher risk of osteoporosis and bone fractures (breaks), particularly if estrogen therapy hasn’t been administered. Scoliosis, affecting about 10% of individuals with TS. Autoimmune Conditions TS elevates the risk of certain autoimmune disorders, such as: Celiac disease. Hashimoto’s thyroid disease (a form of hypothyroidism). Inflammatory bowel disease (IBD). Hearing and Vision Issues Hearing and ear issues commonly found in individuals with TS include: Frequent middle ear infections (otitis media), which can lead to mastoiditis and/or cholesteatoma formation. These often occur between ages 1 and 6. Sensorineural hearing loss, developing in over 50% of adults with TS. The most prevalent vision and eye issues include: Refractive errors (nearsightedness and farsightedness). Crossed eyes (strabismus). Lazy eye (amblyopia). Drooping eyelids (ptosis). Other less common concerns include red-green color blindness and blue sclera. Other Associated Conditions Individuals with Turner syndrome might also experience: Kidney conditions : Structural issues in the kidney-urinary system occur in approximately 30% to 40% of individuals with TS. This may involve horseshoe kidneys or the absence (agenesis) of a kidney. Urine flow problems can lead to urinary tract infections (UTIs). Metabolic syndrome : Individuals with TS have a heightened risk for metabolic syndrome, a collection of conditions that elevate the risk of developing cardiovascular disease, Type 2 diabetes, and stroke. Lymphedema : This condition can result in swollen, puffy hands and feet. Learning disabilities : Those with Turner syndrome typically have normal intelligence levels but face a higher risk of learning disabilities. This often involves difficulties with visual-motor and visual-spatial skills, making it challenging to perceive how objects relate to each other in space. For instance, driving might be difficult. Mental health challenges : Living with Turner syndrome may lead to self-esteem issues and/or chronic stress, potentially causing anxiety and/or depression. Diagnosis and Tests How is Turner syndrome diagnosed? Healthcare providers can diagnose Turner syndrome at any point in a child's development after birth. Occasionally, the condition is detected before birth using the following tests: Noninvasive prenatal testing (NIPT) : This is a screening blood test for the pregnant woman. It looks for signs indicating an increased likelihood of a chromosomal issue with the fetus. Ultrasound during pregnancy : An ultrasound may reveal that the fetus has certain physical features of TS, such as heart problems or fluid around the neck. Additional tests like amniocentesis or chorionic villus sampling may be requested to confirm the diagnosis. Amniocentesis and chorionic villus sampling : These tests examine the amniotic fluid or tissue from the placenta. Providers conduct a genetic test with karyotype analysis on the fluid or tissue, which can confirm if the fetus has Turner syndrome. In other cases, children are diagnosed shortly after birth or during early childhood due to their symptoms. However, some individuals are not diagnosed with Turner syndrome until adulthood. These individuals may experience puberty and menstruation but often have primary ovarian insufficiency (early menopause). After birth, a genetic test with karyotype analysis is used to confirm a Turner syndrome diagnosis. This test requires a blood sample. Management and Treatment How is Turner syndrome treated? Turner syndrome cannot be cured, but various medications and therapies can help manage its symptoms. In addition to addressing related medical issues (such as heart conditions), treatment for Turner syndrome often emphasizes hormones. Treatment options may include: Human growth hormone therapy : Administering human growth hormone injections supports vertical growth. When initiated early, these injections can increase the child’s final height by several inches. Estrogen therapy : Individuals with TS often have low estrogen levels, a hormone crucial for sexual development. Estrogen aids in breast development and menstruation. It also enhances brain development, heart and liver function, and bone health. Cyclic progestins : These medications help induce regular menstrual cycles. Healthcare providers usually start them around ages 11 or 12. Who should be on my child’s care team for Turner syndrome? Treatment for Turner syndrome is tailored to each child’s unique symptoms and development. A coordinated care team offers the most comprehensive and effective care, considering the overall situation and creating a plan tailored to your child. Typically, children with Turner syndrome primarily consult their pediatricians. They also undergo assessment and monitoring by pediatric endocrinologists, who are specialists in hormones and can advise on addressing hormone deficiencies. Other pediatric specialists might include: Cardiologists. Ophthalmologists. Otolaryngologists (ENTs). Nephrologists. Psychologists. Parents can assist the healthcare team by maintaining growth charts and observing other symptoms. Families are also advised to seek genetic counseling. Prevention Is it possible to prevent Turner syndrome? Turner syndrome cannot be prevented. It occurs randomly during conception. Biological parents cannot prevent it, and it is not their fault. Outlook / Prognosis What should I expect if my child has Turner syndrome? It's crucial to understand that each individual with Turner syndrome is affected differently. Predicting its impact on your child is impossible. The best preparation is consulting healthcare providers who specialize in Turner syndrome. What is the life expectancy for someone with Turner syndrome? Individuals with Turner syndrome may have a slightly reduced life expectancy. However, by diagnosing and treating related health conditions, those with Turner syndrome can anticipate a typical lifespan. Living With How can I care for my child with Turner syndrome? Early diagnosis is essential. Monitor your child's growth and developmental milestones. If you notice your child isn't growing as expected or observe unusual physical symptoms, discuss your concerns with their pediatrician. Certain treatments, like hormone therapy, are most effective when started early. It's also vital to address other medical issues, such as cardiac concerns. Regular monitoring and checkups are necessary to track your child's health and any issues. Healthcare providers suggest that children with Turner syndrome: Undergo screening for learning disabilities : This should be done as early as 1 or 2 years old. Collaborating with your child's teachers can help tackle issues before learning disabilities become more severe. Consult a mental health professional : A therapist, such as a child psychologist, can assist with social challenges, low self-esteem, anxiety, and depression. Cognitive-behavioral therapy (CBT), a form of psychotherapy (talk therapy), can aid your child in managing these difficulties. What questions should I ask my doctor? If your child is diagnosed with Turner syndrome, inquire with your healthcare provider about: What treatment options are available? What are the potential risks and benefits of growth hormone injections and other hormone therapies? When should hormone treatments be initiated? What other medical conditions might my child be susceptible to? Which specialists should be included in their care team? What types of learning disabilities might occur? What resources are available to help meet my child’s specific needs?

Pregnenolone ( P5 ), or pregn-5-en-3β-ol-20-one , is an endogenous steroid and a precursor/metabolic intermediate in the biosynthesis of most steroid hormones, including progestogens, androgens, estrogens, glucocorticoids, and mineralocorticoids. Additionally, pregnenolone is biologically active on its own, functioning as a neurosteroid. Besides its role as a natural hormone, pregnenolone has been utilized as a medication and supplement; for more details on pregnenolone as a medication or supplement. Biological function Pregnenolone and its 3β-sulfate, pregnenolone sulfate, like dehydroepiandrosterone (DHEA), DHEA sulfate, and progesterone, are part of the neurosteroids group found in high concentrations in specific brain regions and synthesized there. Neurosteroids influence synaptic functioning, are neuroprotective, and enhance myelinization. Pregnenolone and its sulfate ester may improve cognitive and memory function. Moreover, they may offer protective effects against schizophrenia. Biological activity Neurosteroid activity Pregnenolone acts as an allosteric endocannabinoid, serving as a negative allosteric modulator of the CB1 receptor. It is part of a natural negative feedback mechanism against CB1 receptor activation in animals, preventing full activation by CB1 receptor agonists like tetrahydrocannabinol, the primary active component in cannabis. A related compound, AEF0117, derived from pregnenolone, is more specific for this activity. Pregnenolone has been found to bind with high nanomolar affinity to microtubule-associated protein 2 (MAP2) in the brain. Unlike pregnenolone, pregnenolone sulfate did not bind to microtubules. However, progesterone did, with a similar affinity to pregnenolone, but did not enhance MAP2 binding to tubulin. Pregnenolone was shown to induce tubule polymerization in neuronal cultures and stimulate neurite growth in PC12 cells treated with nerve growth factor. Thus, pregnenolone may regulate microtubule formation and stabilization in neurons, impacting both neural development during prenatal development and neural plasticity during aging. Although pregnenolone itself lacks these activities, its metabolite, pregnenolone sulfate, is a negative allosteric modulator of the GABAA receptor and a positive allosteric modulator of the NMDA receptor. Additionally, pregnenolone sulfate has been shown to activate the transient receptor potential M3 (TRPM3) ion channel in hepatocytes and pancreatic islets, leading to calcium entry and subsequent insulin release. Nuclear receptor activity Pregnenolone acts as an agonist of the pregnane X receptor. Pregnenolone does not exhibit progestogenic, corticosteroid, estrogenic, androgenic, or antiandrogenic activity. Biosynthesis Pregnenolone is synthesized from cholesterol. This conversion involves hydroxylation of the side chain at the C20 and C22 positions, with cleavage of the side chain. The responsible enzyme is cytochrome P450scc, located in the mitochondria, and regulated by anterior pituitary trophic hormones, such as adrenocorticotropic hormone, follicle-stimulating hormone, and luteinizing hormone, in the adrenal glands and gonads. There are two intermediates in cholesterol's transformation into pregnenolone: 22R-hydroxycholesterol and 20α,22R-dihydroxycholesterol. All three steps in the transformation are catalyzed by P450scc. Pregnenolone is mainly produced in the adrenal glands, gonads, and brain. Although pregnenolone is also synthesized in the gonads and brain, most circulating pregnenolone originates from the adrenal cortex. To assay cholesterol to pregnenolone conversion, radiolabeled cholesterol has been utilized. Pregnenolone product can be separated from cholesterol substrate using Sephadex LH-20 minicolumns. Distribution Pregnenolone is lipophilic and easily crosses the blood–brain barrier, unlike pregnenolone sulfate, which does not. Metabolism Pregnenolone undergoes further steroid metabolism in several ways: Pregnenolone can be converted into progesterone. This involves two critical enzyme steps using 3β-hydroxysteroid dehydrogenase and Δ5-4 isomerase. The latter shifts the double bond from C5 to C4 on the A ring. Progesterone enters the Δ4 pathway, leading to 17α-hydroxyprogesterone and androstenedione, precursors to testosterone and estrone. Aldosterone and corticosteroids also derive from progesterone or its derivatives. Pregnenolone can be converted to 17α-hydroxypregnenolone by the enzyme 17α-hydroxylase (CYP17A1). In this Δ5 pathway, the next step is conversion to dehydroepiandrosterone (DHEA) via 17,20-lyase (CYP17A1). DHEA is a precursor of androstenedione. Pregnenolone can be transformed into androstadienol by 16-ene synthase (CYP17A1). Pregnenolone can be converted to pregnenolone sulfate by steroid sulfotransferase, and this conversion can be reversed by steroid sulfatase. Levels Normal circulating levels of pregnenolone are: Men: 10 to 200 ng/dL Women: 10 to 230 ng/dL Children: 10 to 48 ng/dL Adolescent boys: 10 to 50 ng/dL Adolescent girls: 15 to 84 ng/dL Mean levels of pregnenolone do not significantly differ in postmenopausal women and elderly men (40 and 39 ng/dL, respectively). Studies indicate that pregnenolone levels remain largely unchanged after surgical or medical castration in men, aligning with the fact that pregnenolone primarily originates from the adrenal glands. Conversely, medical castration has been found to partially suppress pregnenolone levels in premenopausal women. Similarly, an adrenalectomized premenopausal woman showed only partially reduced circulating pregnenolone levels. Chemistry Pregnenolone, chemically known as pregn-5-en-3β-ol-20-one, like other steroids, consists of four interconnected cyclic hydrocarbons. It contains ketone and hydroxyl functional groups, two methyl branches, and a double bond at C5 in the B cyclic hydrocarbon ring. Like many steroid hormones, it is hydrophobic. The sulfated derivative, pregnenolone sulfate, is water-soluble. 3β-Dihydroprogesterone (pregn-4-en-3β-ol-20-one) is an isomer of pregnenolone, with the C5 double bond replaced by a C4 double bond.

Isolated 17,20-desmolase deficiency is a rare endocrine and autosomal recessive genetic disorder characterized by a complete or partial loss of 17,20-lyase activity, leading to impaired production of androgen and estrogen sex steroids. This condition results in pseudohermaphroditism (partially or fully underdeveloped genitalia) in males, considered a form of intersex, and in both sexes as a reduced or absent puberty/lack of development of secondary sexual characteristics, leading to a somewhat childlike appearance in adulthood if untreated. Unlike combined 17α-hydroxylase/17,20-lyase deficiency, isolated 17,20-lyase deficiency does not affect glucocorticoid production or mineralocorticoid levels, and therefore, does not cause adrenal hyperplasia or hypertension. Symptoms and Signs The symptoms of isolated 17,20-lyase deficiency in males include pseudohermaphroditism (i.e., feminized, ambiguous, or mildly underdeveloped (e.g., micropenis, perineal hypospadias, and/or cryptorchidism (undescended testes)) external genitalia), female gender identity, and in non-complete cases of deficiency where partial virilization occurs, gynecomastia up to Tanner stage V (due to low androgen levels, resulting in a lack of suppression of estrogen); in females, amenorrhoea or, in cases of only partial deficiency, merely irregular menses, and enlarged- cystic ovaries (due to excessive stimulation by high levels of gonadotropins); and in both sexes, hypergonadotropic hypogonadism (hypogonadism despite high levels of gonadotropins), delayed, impaired, or fully absent adrenarche and puberty with an associated reduction in or complete lack of development of secondary sexual characteristics (sexual infantilism), impaired fertility or complete sterility, tall stature (due to delayed epiphyseal closure), eunuchoid skeletal proportions, delayed or absent bone maturation, and osteoporosis. Cause Isolated 17,20-lyase deficiency is a rare disorder caused by genetic mutations in the CYP17A1 gene, without affecting 17α-hydroxylase. This condition is rare, with only a few confirmed cases due to mutations in the CYP17A1 gene. Observed physiological abnormalities include significantly elevated serum levels of progestogens such as progesterone and 17α-hydroxyprogesterone (due to upregulation of precursor availability for androgen and estrogen synthesis), very low or absent peripheral concentrations of androgens such as dehydroepiandrosterone (DHEA), androstenedione, and testosterone and estrogens such as estradiol (due to the lack of 17,20-lyase activity, essential for their production), and high serum concentrations of gonadotropins, follicle-stimulating- hormone (FSH) and luteinizing hormone (LH) (due to a lack of negative feedback because of the absence of sex hormones). Diagnosis The diagnosis of Isolated 17,20-lyase deficiency typically involves several steps, including clinical evaluation, biochemical testing, and genetic analysis. Here are the key components of the diagnostic process: 1. Clinical Evaluation Assessing the patient's symptoms, family history, and any previous medical issues. - Physical Examination: Looking for signs of adrenal insufficiency or abnormal sexual development. 2. Biochemical Testing Measuring serum levels of steroid hormones, particularly: - Dehydroepiandrosterone (DHEA) - Androstenedione - Cortisol - ACTH Stimulation Test: Evaluating adrenal response to adrenocorticotropic hormone (ACTH) to assess adrenal function. 3. Genetic Testing Molecular Analysis: Identifying mutations in the CYP17A1 gene, which encodes the 17,20-lyase enzyme. This can confirm the diagnosis. 4. Imaging Studies In some cases, imaging studies such as ultrasound or MRI may be performed to evaluate adrenal gland morphology. 5. Differential Diagnosis It is essential to rule out other causes of adrenal insufficiency or disorders of sexual development. 6. Consultation with Specialists Referral to an endocrinologist for specialized evaluation and management may be necessary. By combining these approaches, healthcare providers can accurately diagnose Isolated 17,20-lyase deficiency and develop an appropriate treatment plan. Treatment Males and females may undergo hormone replacement therapy (i.e., with androgens and estrogens, respectively), leading to normal sexual development and alleviating most symptoms. For 46,XY (genetically male) individuals who are phenotypically female and/or identify as female, estrogen treatment is recommended. In 46,XY females, removal of undescended testes should be performed to prevent malignant degeneration, while in 46,XY males, surgical correction of the genitals is generally necessary, and if needed, an orchidopexy (relocation of undescended testes to the scrotum) may be performed. For genetic females with ovarian cysts, GnRH analogues may be used to manage high FSH and LH levels if unresponsive to estrogens.