Uterus didelphys (from Ancient Greek di- 'two' and delphus 'womb'; sometimes also uterus didelphis ) is a uterine malformation where the uterus appears as a paired organ due to the failure of the embryogenetic fusion of the Müllerian ducts. This results in a double uterus with two separate cervices, and possibly a double vagina. Each uterus has a single horn connected to the ipsilateral fallopian tube that faces its ovary. Most non-human mammals have a non-single uterus with separated horns. Marsupials and rodents possess a double uterus (uterus duplex). In other animals ( e.g. nematodes), 'didelphic' refers to a double genital tract, unlike monodelphic, which has a single tract. Signs and symptoms Women with this condition may be asymptomatic and unaware of having a double uterus. However, a study by Heinonen indicated that certain conditions are more prevalent. In his study of 26 women with a double uterus, gynecological complaints included dysmenorrhea and dyspareunia. All patients had a double vagina. The fetal survival rate in 18 patients who delivered was 67.5%. Premature delivery occurred in 21% of the pregnancies. Breech presentation was noted in 43% of women, and cesarean section was performed in 82% of the cases. Cause The uterus is formed during embryogenesis by the fusion of the two paramesonephric ducts (also known as Müllerian ducts). This process typically merges the two Müllerian ducts into a single uterine body but does not occur in affected women, who retain their double Müllerian systems. A didelphic uterus will have a double cervix and is often associated with a double vagina. The reason for the fusion failure is unknown. Associated defects may impact the vagina, the renal system, and less commonly, the skeleton. The condition is less common than other uterine malformations such as arcuate uterus, septate uterus, and bicornuate uterus. It is estimated to occur in 1/3,000 women.[2] Syndrome A specific combination of uterus didelphys (double uterus), unilateral hematocolpos (inadequate drainage of menstrual blood), and ipsilateral renal agenesis (having only one kidney) has been noted. Diagnosis A pelvic examination will typically reveal a double vagina and a double cervix. Investigations are usually initiated based on such findings and when reproductive issues arise. Not all cases of uterus didelphys involve duplication of the cervix and vagina. Useful techniques to examine the uterine structure include transvaginal ultrasonography, sonohysterography, hysterosalpingography, MRI, and hysteroscopy. Recently, 3-D ultrasonography has been recommended as an excellent non-invasive method to assess uterine malformations. Uterus didelphys is often mistaken for a complete uterine septum. Multiple investigation methods are often needed to accurately diagnose the condition. Accurate diagnosis is vital as treatments for these conditions differ significantly. While most doctors suggest removing a uterine septum, they generally agree that surgery on a uterus didelphys is not advisable. In either case, consulting a highly qualified reproductive endocrinologist is recommended. Management Patients with a double uterus may require special care during pregnancy as premature birth and malpresentation are common. Cesarean section was performed in 82% of patients reported by Heinonen. Uterus didelphys has also been associated with higher rates of infertility, miscarriage, intrauterine growth retardation, and postpartum bleeding in certain studies. Epidemiology In the United States, uterus didelphys is reported to occur in 0.1–0.5% of women. The exact prevalence of this anomaly is difficult to determine, as it may go undetected in the absence of medical and reproductive complications. Multiple pregnancy There have been cases where twin gestations occurred with each uterus carrying its own pregnancy. Approximately 100 cases worldwide have been reported of a woman with a double uterus being pregnant in both wombs simultaneously. Before 2005, only 11 such cases had been documented globally. It is possible for deliveries to occur at different times, with intervals ranging from days to weeks. Maricia Tescu of Iași, Romania, gave birth to a premature son on December 11, 2004. Her second son was born via C-section at full term 59 days later, in early February 2005. On February 26, 2009, Sarah Reinfelder of Sault Ste. Marie, Michigan, delivered two healthy, although seven weeks premature, infants by cesarean section at Marquette General Hospital. On September 15, 2011, Andreea Barbosa of St. Petersburg, Florida, gave birth to fraternal twins, a boy and a girl, via C-section. On October 23, 2020, Kelly Fairhurst of Essex, England, delivered twins, a boy and a girl, at 35 weeks via a planned C-section. On December 19 and 20, 2023, Kelsey Hatcher delivered fraternal twin girls at 39 weeks, with one girl delivered vaginally and the other by C-section the next day, at the University of Alabama at Birmingham Hospital. Triplets A UK woman with a double uterus gave birth to triplets in 2006. Hannah Kersey, of Northam, Devon, gave birth to a pair of identical twin girls from an egg that implanted into one womb and then divided, and to a female infant from a single egg that implanted into the other womb. This was the first known birth of viable triplets in a woman with a double uterus. A triplet pregnancy in a woman with uterus didelphys was reported from Israel in 1981; one baby died in utero, and of the remaining babies, one was delivered at 27 weeks gestation and the other 72 days later. In 2019, Arifa Sultana of Bangladesh gave premature birth in February and then via emergency Caesarean section to twins, 26 days later.

WNT4 deficiency is a rare genetic condition affecting females, leading to the underdevelopment or absence of the uterus and vagina. It is caused by mutations in the WNT4 gene. Elevated androgen levels in the blood can trigger the development of male characteristics, such as male-pattern hair growth on the chest and face. Individuals with this genetic defect develop breasts but do not menstruate. Mayer–Rokitansky–Küster–Hauser syndrome is a related but distinct condition. Some women initially diagnosed with MRKH are later found to have WNT4 deficiency. Most women with MRKH syndrome do not have WNT4 gene mutations. The absence of menstruation may be the first clinical sign of WNT4 deficiency, which can cause significant psychological challenges, and counseling is recommended. Signs and symptoms Due to the rarity of WNT4 deficiency, case reports are scarce, making it difficult to compile a comprehensive list of signs and symptoms. More cases need to be identified to better understand the potential spectrum of associated symptoms. However, from identified cases and the mechanism of action, certain symptoms have been characterized to explain WNT4 deficiency. Failure to begin menstrual cycles (amenorrhea) Ambiguous genitalia (short vagina, severely underdeveloped/absent uterus) but normal pubertal characteristics like breast development and pubic hair Infertility Difficulty with sexual intercourse Pain during intercourse Abnormally high levels of androgens in the blood (hyperandrogenism) Possible development of acne and male-pattern hair growth, including facial/chest hair (hirsutism) Prone to urinary tract infections and/or kidney stones Causes WNT4 deficiency is a very rare disorder affecting females, caused by mutations in the WNT4 gene found on chromosome 1. This gene promotes female sex development and suppresses male sex development, providing instructions for producing a protein responsible for forming the female reproductive system, kidneys, and several hormone-producing glands. The WNT4 protein regulates the formation of the Müllerian ducts, which develop into the uterus, fallopian tubes, cervix, and upper part of the vagina. It is also crucial for the development of ovaries and oocytes (female egg cells). This disorder may result from a random spontaneous mutation or be inherited as an autosomal dominant trait. Dominant genetic disorders occur when a single copy of an abnormal gene is enough to express its phenotypic traits. While the abnormal gene can be inherited from either parent, it cannot be inherited from the mother due to infertility. It is unclear if the mutation can be inherited from the father or arises from new mutations in the gene. WNT4 is a secreted protein encoded by the WNT4 gene on chromosome 1, located at (1p35). The functions of the WNT4 protein are not fully understood, and more research is needed to determine the underlying mechanism causing the symptoms associated with this disease. WNT4 is known to bind to the frizzled family of receptors, resulting in the transcriptional regulation of target genes. Frizzled receptors are atypical G protein-coupled receptors involved in the Wnt signaling pathway and others. WNT4 is produced in ovarian somatic cells and up-regulates the Dax1 gene, inhibiting steroidogenic enzymes. It increases follistatin expression, inhibiting anti-testis action and supporting ovarian germ cell survival. Diagnosis WNT4 deficiency is congenital, present at birth, but may remain undiagnosed until adolescence when female puberty begins. The onset of the menstrual cycle marks puberty, but primary amenorrhea (lack of menstruation) might prompt a visit to a physician and initiate diagnosis. Due to its rarity, WNT4 deficiency may be suspected only after extensive clinical evaluation, detailed patient history, and identification of characteristic symptoms, such as an absent or underdeveloped uterus and/or vagina with normal external genitalia. Specialized imaging techniques like ultrasounds or magnetic resonance imaging (MRI) can visualize internal organs (uterus, ovaries, and kidney) to confirm WNT4 deficiency. Modern science allows molecular genetic analysis to reveal WNT4 gene mutations and confirm the diagnosis. Karyotyping can also be performed to rule out other conditions by examining chromosome integrity in a cell sample. A female with WNT4 deficiency will have a normal 46, XX karyotype, but abnormalities on those chromosomes may be present. Related disorders / common misdiagnoses WNT4 deficiency can be misdiagnosed due to similar symptoms with other disorders. One such disorder is Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. Women with WNT4 deficiency are sometimes misdiagnosed with MRKH syndrome due to similar signs and symptoms. The main difference is that in MRKH syndrome, there is no WNT4 gene mutation, despite underdevelopment of the uterus/vagina and amenorrhea, while maintaining normal ovarian function. MRKH syndrome is often the initial diagnosis, but extensive genetic testing and imaging analysis can confirm WNT4 deficiency. Additionally, complete androgen insensitivity syndrome is a rare disorder where individuals are genetically male (46, XY) but do not respond to androgens. This syndrome presents intersex characteristics, as the person appears female externally but is genetically male with a 46, XY karyotype. Prevention/treatment WNT4 is a congenital disease with autosomal dominant inheritance, so prevention is not possible. With an absent uterus, conceiving is not an option, but other conception methods may be available due to functional ovaries. Genetic testing might be recommended to prevent passing the gene, given its autosomal dominant inheritance. Treatment is still evolving, as few cases have been reported and severity varies. Treatment focuses on specific symptoms for each individual, requiring a team of specialists such as pediatricians (for diagnoses under age 18), internists, gynecologists, nephrologists, endocrinologists, plastic surgeons, urologists, psychiatrists, and others. Counseling Genetic Testing Antibiotics to treat recurrent UTIs Non-Surgical techniques like vaginal dilators to increase vaginal depth, easing pain and difficulty during intercourse Franck's Dilator Method - involves applying the vaginal dilator for up to 6 weeks to several months to stretch and widen the vaginal walls Plastic Surgery Vaginoplasty to create an artificial vagina Prognosis Due to the rarity of this disorder, prognosis evidence is limited. However, women diagnosed with WNT4 deficiency may live long lives. The diagnosis leads to infertility, difficulty with intercourse, and recurring kidney stones, which may affect quality of life. Extensive counseling and group therapy might be necessary to adapt to a different lifestyle. Epidemiology Concrete epidemiological evidence for WNT4 deficiency is lacking due to its rarity. The most solid evidence is its autosomal dominant inheritance pattern and the mutation on chromosome 1. No evidence shows population favorability, distribution patterns, risk factors, or environmental factors. Current research/research directions WNT4 deficiency is an extremely rare genetic disorder, and there is limited research available specifically on the disease. Although there is an understanding of the gene and its function in the body, the scarcity of cases makes it challenging to conduct extensive research on the disorder. However, future research on the WNT4 gene could be valuable for evaluating conditions like polycystic ovary disease/syndrome (PCOS), a common condition affecting many women. PCOS also exhibits hyperandrogenic traits, and a better understanding of the milder form of WNT4 and its signaling pathways in ovarian tissues could help clarify its role in the hyperandrogenic states observed in PCOS patients. Research on the WNT4 gene is ongoing in relation to other conditions linked to its properties. Despite the rarity of this disorder, the WNT4 gene plays a significant role in various biological functions. For example, in 2016, researchers investigated how the WNT4 gene influences estrogen receptor signaling and endocrine resistance in invasive lobular carcinoma cell lines. As a crucial signaling molecule in mammary gland development regulated by a progesterone receptor, the WNT4 pathway has been utilized in breast cancer research to modulate the endocrine response in invasive lobular carcinoma. Additionally, the WNT4 gene is involved in research concerning kidney function. In 2013, DiRocco et al. published a study on WNT4 and beta-catenin signaling in medullary kidney fibroblasts, revealing that WNT4 expression in renal fibrosis is crucial in the proliferation process.

Estrogen receptors ( ERs ) are proteins within cells that serve as receptors for the hormone estrogen (17β-estradiol). There are two main categories of ERs. The first includes intracellular estrogen receptors, specifically ERα and ERβ, part of the nuclear receptor family. The second category consists of membrane estrogen receptors (mERs), such as GPER (GPR30), ER-X, and Gq-mER, primarily G protein-coupled receptors. When estrogen activates intracellular ERs, they relocate to the nucleus and attach to specific DNA sequences. As DNA-binding transcription factors, they regulate various genes. However, ERs also have functions independent of DNA binding, contributing to the diverse effects of estrogen signaling in cells. Estrogen receptors (ERs) belong to the steroid hormone receptors family, which includes hormone receptors for sex steroids. Alongside androgen receptors (ARs) and progesterone receptors (PRs), ERs are crucial for regulating sexual maturation and gestation. These receptors mediate their respective hormones' effects, aiding in the development and maintenance of reproductive functions and secondary sexual characteristics. Genes In humans, the two forms of the estrogen receptor are encoded by different genes, ESR1 and ESR2 , located on the sixth and fourteenth chromosomes (6q25.1 and 14q23.2), respectively. Structure Estrogen receptors exist in two forms, usually referred to as α and β , each encoded by a separate gene ( ESR1 and ESR2 , respectively). Hormone-activated estrogen receptors form dimers, and since both forms are coexpressed in many cell types, the receptors may form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers. Estrogen receptor alpha and beta show significant overall sequence estrogen hormone. While this region can activate gene transcription without a ligand, this activation is weak and more selective compared to the activation provided by the E domain. The C domain, also known as the DNA-binding domain, binds to estrogen response elements in DNA. The D domain is a hinge region connecting the C and E domains. The E domain contains the ligand binding cavity and binding sites for coactivator and corepressor proteins. The E-domain in the presence of bound ligand can activate gene transcription. The function of the C-terminal F domain is not entirely clear and varies in length. Due to alternative RNA splicing, several ER isoforms exist. At least three ERα and five ERβ isoforms have been identified. The ERβ isoforms receptor subtypes can transactivate transcription only when forming a heterodimer with the functional ERß1 receptor of 59 kDa. The ERß3 receptor was detected at high levels in the testis. The two other ERα isoforms are 36 and 46kDa. Only in fish, but not in humans, an ERγ receptor has been described. Tissue distribution Both ERs are widely expressed in different tissue types, though their expression patterns show some notable differences: The ERα is found in the endometrium, breast cancer cells, ovarian stromal cells, and the hypothalamus. In males, ERα protein is found in the epithelium of the efferent ducts. The expression of the ERβ protein has been documented in ovarian granulosa cells, kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, and endothelial cells. ERs are considered cytoplasmic receptors in their unliganded state, but visualization research has shown that only a small fraction of ERs reside in the cytoplasm, with most ER constitutively in the nucleus. The "ERα" primary transcript gives rise to several alternatively spliced variants of unknown function. Signal transduction As a steroidal hormone, estrogen can easily diffuse through the phospholipid membranes of cells due to its lipophilic nature. Consequently, estrogen receptors can be located intracellularly and do not necessarily need to be membrane-bound to interact with estrogen. However, both intracellular and membrane-bound estrogen receptors exist, each mediating different cellular responses to estrogen. Genomic In the absence of hormone, estrogen receptors are predominantly located in the cytoplasm. Hormone binding triggers a series of events, beginning with the migration of the receptor from the cytoplasm to the nucleus. This is followed by the dimerization of the receptor, where two receptor molecules join together. Finally, the receptor dimer binds to specific DNA sequences known as hormone response elements, initiating the process of gene regulation. The DNA/receptor complex then recruits other proteins responsible for transcription of downstream DNA into mRNA and ultimately protein, resulting in changes in cell function. Estrogen receptors are also present within the cell nucleus, and both estrogen receptor subtypes (ERα and ERβ) contain a DNA-binding domain, allowing them to function as transcription factors regulating protein production. The receptor also interacts with transcription factors such as activator protein 1 and Sp-1 to promote transcription, via several coactivators including PELP-1. Tumor suppressor kinase LKB1 coactivates ERα in the cell nucleus through direct binding, recruiting it to the promoter of ERα-responsive genes. LKB1's catalytic activity enhances ERα transactivation compared to catalytically deficient LKB1 mutants. Direct acetylation of estrogen receptor alpha at lysine residues in the hinge region by p300 regulates transactivation and hormone sensitivity. Non-genomic Nuclear estrogen receptors can also associate with the cell surface membrane and undergo rapid activation upon cellular exposure to estrogen. Some ERs interact with cell membranes by binding to caveolin-1 and forming complexes with G proteins, striatin, receptor tyrosine kinases (e.g., EGFR and IGF-1), and non-receptor tyrosine kinases (e.g., Src). Membrane-bound ERs associated with striatin can increase levels of Ca2+ and nitric oxide (NO). Interactions with receptor tyrosine kinases trigger signaling to the nucleus via the mitogen-activated protein kinase (MAPK/ERK) and phosphoinositide 3-kinase (Pl3K/AKT) pathways. Glycogen synthase kinase-3 (GSK)-3β inhibits nuclear ER transcription by preventing phosphorylation of serine 118 on nuclear ERα. The PI3K/AKT and MAPK/ERK pathways can phosphorylate GSK-3β, thereby removing its inhibitory effect, with the latter pathway acting via rsk. 17β-Estradiol has been shown to activate the G protein-coupled receptor GPR30. However, the subcellular localization and precise role of this receptor remain controversial. Cancer Estrogen receptors are over-expressed in around 70% of breast cancer cases, referred to as "ER-positive," and can be demonstrated in such tissues using immunohistochemistry. Two hypotheses have been proposed to explain why this causes tumorigenesis, and the available evidence suggests that both mechanisms contribute: First, binding of estrogen to the ER stimulates proliferation of mammary cells, with the resulting increase in cell division and DNA replication, leading to mutations. Second, estrogen metabolism produces genotoxic waste. The result of both processes is disruption of cell cycle, apoptosis, and DNA repair, which increases the chance of tumor formation. ERα is certainly associated with more differentiated tumors, while evidence that ERβ is involved is controversial. Different versions of the ESR1 gene have been identified (with single-nucleotide polymorphisms) and are associated with different risks of developing breast cancer. Estrogen and the ERs have also been implicated in breast cancer, ovarian cancer, colon cancer, prostate cancer, and endometrial cancer. Advanced colon cancer is associated with a loss of ERβ, the predominant ER in colon tissue, and colon cancer is treated with ERβ-specific agonists. Endocrine therapy for breast cancer involves selective estrogen receptor modulators (SERMS), such as tamoxifen, which behave as ER antagonists in breast tissue, or aromatase inhibitors, such as anastrozole. ER status is used to determine sensitivity of breast cancer lesions to tamoxifen and aromatase inhibitors. Another SERM, raloxifene, has been used as a preventive chemotherapy for women judged to have a high risk of developing breast cancer. Another chemotherapeutic anti-estrogen, ICI 182,780 (Faslodex), which acts as a complete antagonist, also promotes degradation of the estrogen receptor. However, de novo resistance to endocrine therapy undermines the efficacy of using competitive inhibitors like tamoxifen. Hormone deprivation through the use of aromatase inhibitors is also rendered futile. Massively parallel genome sequencing has revealed the common presence of point mutations on ESR1 that are drivers for resistance, and promote the agonist conformation of ERα without the bound ligand. Such constitutive, estrogen-independent activity is driven by specific mutations, such as the D538G or Y537S/C/N mutations, in the ligand binding domain of ESR1 and promote cell proliferation and tumor progression without hormone stimulation. Menopause The metabolic effects of estrogen in postmenopausal women have been linked to the genetic polymorphism of estrogen receptor beta (ER-β). Aging Studies in female mice have shown that estrogen receptor-alpha declines in the pre-optic hypothalamus as they grow old. Female mice that were given a calorically restricted diet during the majority of their lives maintained higher levels of ERα in the pre-optic hypothalamus than their non-calorically restricted counterparts. Obesity A dramatic demonstration of the importance of estrogens in the regulation of fat deposition comes from transgenic mice that were genetically engineered to lack a functional aromatase gene. These mice have very low levels of estrogen and are obese. Obesity was also observed in estrogen-deficient female mice lacking the follicle-stimulating hormone receptor. The effect of low estrogen on increased obesity has been linked to estrogen receptor alpha. SERMs for other treatment purposes SERMs are also being studied for the treatment of uterine fibroids and endometriosis. The evidence supporting the use of SERMs for treating uterine fibroids (reduction in size of fibroids and improving other clinical outcomes) is inconclusive and more research is needed. It is also not clear if SERMs are effective for treating endometriosis. Estrogen insensitivity syndrome Estrogen insensitivity syndrome is a rare intersex condition with 5 reported cases, in which estrogen receptors do not function. The phenotype results in extensive masculinization. Unlike androgen insensitivity syndrome, EIS does not result in phenotype sex reversal. It is incredibly rare and is analogous to the AIS, and forms of adrenal hyperplasia. The reason why AIS is common and EIS is exceptionally rare is that XX AIS does not result in infertility, and therefore can be maternally inherited, while EIS always results in infertility regardless of karyotype. A negative feedback loop between the endocrine system also occurs in EIS, in which the gonads produce markedly higher levels of estrogen for individuals with EIS (119–272 pg/mL XY and 750–3,500 pg/mL XX, see average levels) however no feminizing effects occur. Binding and functional selectivity The ER's helix 12 domain plays a crucial role in determining interactions with coactivators and corepressors and, therefore, the respective agonist or antagonist effect of the ligand. Different ligands may differ in their affinity for alpha and beta isoforms of the estrogen receptor: estradiol binds equally well to both receptors estrone, and raloxifene bind preferentially to the alpha receptor estriol, and genistein to the beta receptor Subtype selective estrogen receptor modulators preferentially bind to either the α- or the β-subtype of the receptor. In addition, the different estrogen receptor combinations may respond differently to various ligands, which may translate into tissue-selective agonistic and antagonistic effects. The ratio of α- to β- subtype concentration has been proposed to play a role in certain diseases. The concept of selective estrogen receptor modulators is based on the ability to promote ER interactions with different proteins such as transcriptional coactivator or corepressors. Furthermore, the ratio of coactivator to corepressor protein varies in different tissues. As a consequence, the same ligand may be an agonist in some tissue (where coactivators predominate) while antagonistic in other tissues (where corepressors dominate). Tamoxifen, for example, is an antagonist in breast and is, therefore, used as a breast cancer treatment but an ER agonist in bone (thereby preventing osteoporosis) and a partial agonist in the endometrium (increasing the risk of uterine cancer).

XXYY syndrome is a sex chromosome anomaly where males have two extra chromosomes: one X and one Y. Typically, human cells contain two sex chromosomes, one from each parent. Females usually have two X chromosomes (XX), while males have one X and one Y chromosome (XY). The presence of at least one Y chromosome with a functional SRY gene determines maleness. Thus, individuals with XXYY are genotypically male. Males with XXYY syndrome possess 48 chromosomes instead of the usual 46, leading to the designation 48, XXYY syndrome or 48, XXYY . This condition affects approximately one in every 18,000–40,000 male births. Signs and Symptoms Common signs and symptoms of this condition include: Azoospermia Decreased testicular size Developmental delays Hypergonadotropic hypogonadism Sterility Intellectual impairment Speech impairment Other frequent signs include: Abnormal dental enamel morphology Abnormal shoulder morphology Anxiety Asthma Attention-deficit hyperactivity disorder (ADHD) symptoms Autism spectrum disorders Blepharophimosis Caries Clinodactyly Constipation Delayed tooth eruption Depression Chronic otitis media Elbow dislocation Epicanthus Flat occiput Gynecomastia Hypertelorism Low muscle tone Joint hyperflexibility Obesity Open bite Flat feet Radioulnar synostosis Strabismus Tall stature Taurodontism Tremor Additional symptoms may include: Learning disabilities Scoliosis Undescended testes Low testosterone Cause 48,XXYY syndrome is associated with the X and Y chromosomes. Typically, individuals have 46 chromosomes in each cell. Two of these, the X and Y chromosomes, determine male or female sex characteristics. Females generally have two X chromosomes (46,XX), and males have one X and one Y chromosome (46,XY). 48,XXYY syndrome arises from an extra copy of both sex chromosomes in a male's cells (48,XXYY). Extra genes on the X chromosome disrupt male sexual development, impairing normal testicular function and reducing testosterone levels. Many genes are exclusive to the X or Y chromosome, but those in the pseudoautosomal regions exist on both. Extra copies from these regions contribute to the syndrome's signs and symptoms, though specific genes remain unidentified. Genetics The 48,XXYY condition is not inherited; it typically occurs randomly during the formation of reproductive cells (eggs and sperm). An error in cell division, called nondisjunction, leads to a reproductive cell with an abnormal chromosome count. In 48,XXYY syndrome, the extra sex chromosomes usually originate from a sperm cell. Nondisjunction can result in a sperm cell with two extra sex chromosomes, creating a sperm cell with three sex chromosomes (one X and two Y chromosomes). If this sperm fertilizes a normal egg with one X chromosome, the child will have two X and two Y chromosomes in each cell. In a few cases, 48,XXYY syndrome results from nondisjunction of sex chromosomes in a 46,XY embryo shortly after fertilization. A normal sperm with one Y chromosome fertilizes a normal egg with one X chromosome, but post-fertilization nondisjunction adds two extra sex chromosomes, forming a 48,XXYY embryo. Diagnosis A karyotype is used to diagnose XXYY syndrome. Treatment involves medications, behavioral therapies, and extensive community support. Management Patients typically require monitoring by an endocrinologist. If hypogonadism is present, testosterone treatment should be considered for all, regardless of cognitive abilities, due to benefits for bone health, muscle strength, fatigue, and endurance, along with potential mental health improvements. Most children with XXYY experience developmental delays and learning disabilities, necessitating evaluations in psychology, speech/language therapy, occupational therapy, and physical therapy. Consultation with a developmental pediatrician, psychiatrist, or neurologist is advised to develop a treatment plan including therapies, interventions, educational supports, and psychotropic medications for behavioral and psychiatric symptoms. Common diagnoses like learning disability/ID, ADHD, autism spectrum disorders, mood disorders, tic disorders, and other mental health issues should be considered, screened for, and treated. Standard medications for inattention, impulsivity, anxiety, and mood instability often yield positive outcomes in this group, enhancing academic progress, emotional wellbeing, and long-term prospects. Poor fine-motor coordination and intention tremor development can make handwriting challenging, so early introduction of occupational therapy and keyboarding is recommended to aid schoolwork and self-help skills. Educational difficulties require a full psychological evaluation to identify verbal and performance skill discrepancies and individual academic needs. Expressive language skills often remain affected throughout life, necessitating speech therapy for expressive language skills, dyspraxia, and language pragmatics into adulthood. Weak adaptive skills (life skills) demand community-based support for nearly all adults. Additional treatment recommendations may be needed based on individual strengths and weaknesses in XXYY syndrome. Prognosis Patients generally have a normal life expectancy but require regular medical follow-ups.

XXXY syndrome is a genetic condition marked by an abnormal number of sex chromosomes, where individuals have two additional X chromosomes. Typically, people possess two sex chromosomes: either an X and a Y or two X chromosomes. The presence of a Y chromosome with a functional SRY gene triggers the expression of genes responsible for male characteristics. Consequently, XXXY syndrome affects only males. The extra two X chromosomes in males with XXXY syndrome result in a total of 48 chromosomes, rather than the usual 46. Hence, XXXY syndrome is often called 48,XXXY. This syndrome is associated with a wide range of symptoms, including cognitive and behavioral issues, taurodontism, and infertility. It generally arises from a new mutation in one of the parent's gametes, as affected individuals are typically infertile. XXXY syndrome is estimated to occur in one out of every 50,000 male births. Signs and symptoms The symptoms of 48,XXXY syndrome are akin to those of Klinefelter syndrome, although they are usually more severe in 48,XXXY syndrome. Similar to Klinefelter syndrome, the presence of extra X chromosomes impacts the male reproductive system, can lead to physical abnormalities, and may affect cognitive development. Comparing 47,XXY with 48,XXXY, there is a higher risk of congenital malformations and more medical issues in those with 48,XXXY. Reproductive Individuals with XXXY syndrome may experience testicular dysgenesis and hypergonadotrophic hypogonadism. Testicular dysgenesis involves incomplete or complete loss of spermatogenesis, leading to very low or absent sperm production, resulting in infertility. Hypergonadotrophic hypogonadism is a condition where the testicular function is reduced, potentially causing low levels of sex steroids like testosterone. Physical Males with 48,XXXY may have average or tall stature, which becomes more noticeable in adulthood. Facial dysmorphism is common, including increased distance between the eyes (hypertelorism), skin folds of the upper eyelid (epicanthal folds), up-slanting eyelid openings (palpebral fissures), and hooded eyelids. Other features include the fifth finger bending inward towards the fourth finger (clinodactyly), short nail beds, flat feet, double jointedness (hyperextensibility), and prominent elbows with cubitus varus, where the arm is closer to the body. Musculoskeletal features may include congenital elbow dislocation and limited inward foot rolling while walking and upon landing. Micropenis is another common symptom. Those with XXXY are also prone to taurodontism, which often appears early and can be an early sign of XXY syndrome. They are also susceptible to hip dysplasia and other joint abnormalities. Symptoms vary due to differing androgen deficiencies and change with age. Prepubescent boys with XXXY syndrome may not differ in appearance from children without the syndrome, likely because androgen levels are similar among prepubescent boys, but differences arise during puberty. Those with XXXY syndrome may also experience a feminine distribution of body fat, and gynecomastia may be present. Tall stature is more likely to appear in adolescence when androgen levels begin to differ between those with and without XXXY syndrome. Cognitive and developmental Neurological effects are thought to be more severe as the number of extra X chromosomes increases; a male with 48,XXXY is likely to have more severe symptoms than one with Klinefelter syndrome. Developmental delays are common in infancy and childhood, including speech delays, motor delays, and hypotonia (lack of muscle tone), also known as floppy baby syndrome. Individuals with XXXY syndrome show cognitive and behavioral problems. Patients typically exhibit altered adaptive behavior, which is the ability to demonstrate essential living skills, including social skills, community living, safety, functional use of academic skills, and self-care. People with XXXY syndrome score significantly lower in daily living skills and communication domains compared to XXYY and XXY individuals, indicating limited abilities in self-care, social skills, safety, academic skills application, and responsibility. Individuals with this syndrome also experience emotional symptoms such as anxiety, obsessive-compulsive behaviors, behavioral dysregulation, and emotional immaturity. Typically, they have an IQ range of 40–60, whereas the average IQ range is 95–110. They also face language-based learning disabilities affecting their communication. Those with XXXY syndrome tend to exhibit fewer externalizing and internalizing behaviors than those with 48,XXYY syndrome, which may positively affect their social functioning. These individuals may also be more vulnerable to autistic features. Changes in testosterone and androgen deficits may influence their social behaviors, increasing the risk of autistic features. Cause The cause of 48,XXXY can result from non-disjunction in the paternal sperm or the maternal oocyte. The most likely scenario for this aneuploidy is equal contribution from each parent, with the egg providing an XX and the sperm an XY. If the sperm is the genetic cause of 48,XXXY syndrome, it would contain two X chromosomes and one Y chromosome due to two nondisjunction events during spermatogenesis, in both meiosis I and II. The duplicated X chromosome in the sperm would fail to separate in both meiosis I and II, resulting in a sperm containing both X and Y chromosomes. This XXY sperm would fertilize a normal oocyte to create a XXXY zygote. If the oocyte is the genetic cause of 48,XXXY syndrome, it would have three X chromosomes due to two nondisjunction events during oogenesis. In meiosis I, both sets of duplicated X chromosomes would not separate. Then, in meiosis II, one set of X chromosomes would not separate, while the other would, resulting in an oocyte with three X chromosomes. A normal sperm with a Y chromosome would fertilize the XXX oocyte to form a XXXY zygote. Mechanism The additional X chromosomes characteristic of this condition are linked to an androgen deficiency, leading to reduced or absent feedback inhibition of the pituitary gland and elevated gonadotropin levels. Diagnosis 48,XXXY is usually diagnosed through a standard karyotype, a chromosomal analysis showing an individual's full set of chromosomes. Another diagnostic method is chromosomal microarray to detect extra X chromosomes. Chromosomal microarray (CMA) identifies extra or missing chromosomal segments or whole chromosomes using microchip-based DNA analysis. Males with 48,XXXY are diagnosed from before birth to adulthood, depending on symptom severity. The age range at diagnosis is likely due to the rarity of XXXY syndrome and its less extreme phenotypes compared to other Klinefelter syndrome variants (such as XXXXY). Diagnostic testing can also be performed via blood samples. Elevated follicle stimulating hormone, luteinizing hormone levels, and low testosterone levels can indicate this syndrome. Management Treatment Various treatments exist for the symptoms of XXXY syndrome. Testosterone therapy, involving regular testosterone doses, has been shown to improve some physical and psychological symptoms. However, it may have negative side effects, such as worsening behavior and osteoporosis. Not all individuals are suitable for testosterone therapy, as the best results occur when treatment begins at puberty onset, and diagnosis often occurs later or not at all. Testosterone therapy does not improve fertility. The psychological profile of individuals with XXXY should be considered in treatment, as these traits affect treatment compliance. Early detection of Taurodontism allows for successful root canal treatment. Planning to prevent Taurodontism is possible, but early diagnosis of this syndrome is uncommon. Taurodontism can be an early indicator of XXXY syndrome before other characteristics develop. Surgical treatments for joint problems, like hip dysplasia, are common and often successful with physiotherapy. Individuals with XXXY syndrome can also attend speech therapy to help them understand and use more complex language. This therapy is beneficial for those with severe speech delays, improving communication with others. Since hypotonia is common in this syndrome, physical therapy can help develop muscle tone, balance, and coordination. Quality of life In mild cases, individuals with XXXY syndrome may lead relatively good lives. They may face communication difficulties due to language-based deficits, making relationship-building challenging, but fulfilling relationships are still achievable. Those with higher adaptive functioning scores are likely to have a better quality of life due to their independence. Genetic counselling As the syndrome results from a chromosomal non-disjunction event, the recurrence risk is not significantly higher than in the general population. There is no evidence suggesting non-disjunction occurs more frequently in specific families. XXXY syndrome

XXXXY syndrome , also referred to as 49,XXXXY syndrome or Fraccaro syndrome , is a very rare aneuploidic sex chromosomal disorder. It affects approximately 1 in 85,000 to 100,000 males. This condition is caused by maternal non-disjunction during both meiosis I and II. First identified in 1960, it was named Fraccaro syndrome after the researcher who discovered it. Signs and symptoms The symptoms of 49,XXXXY bear some resemblance to those of Klinefelter syndrome and 48,XXXY, but they are generally more severe. Aneuploidy is often lethal, but due to "X-inactivation", the impact of the extra gene dosage from additional X chromosomes is significantly reduced. Reproductive Individuals with 49,XXXXY syndrome typically show underdeveloped secondary sex characteristics and experience sterility in adulthood. Hypoplastic genitalia Absent or delayed puberty Physical Males with 49,XXXXY often have multiple skeletal anomalies, including: Genu valgum Pes cavus Fifth finger clinodactyly Other effects include: Cleft palate Club feet Respiratory conditions Short and/or broad neck Low birth weight Hyperextensible joints Short stature Narrow shoulders Coarse features in older age Hypertelorism Epicanthal folds Prognathism Gynecomastia (rare) Muscular hypotonia Cryptorchidism Congenital heart defects A very round face in infancy 49,XXXXY may also be linked to higher rates of primary immunodeficiency. Cognitive and developmental Similar to Down syndrome, the cognitive effects of 49,XXXXY syndrome vary. Impaired speech and maladaptive behavioral issues are common. A study examined males diagnosed with 48,XXYY, 48,XXXY, and 49,XXXXY, finding that males with 48,XXXY and 49,XXXXY operate at a much lower cognitive level than their peers. These individuals also tend to display behavior that is less mature for their age, with increased aggressive tendencies noted in the study. A 2020 study revealed that boys with 49,XXXXY exhibit higher rates of internalizing behavior and anxiety, starting as early as preschool. Tests using the Social Responsiveness Scale-2 (SRS-2) indicated that while individuals with the condition generally showed more signs of social impairment, their social awareness was minimally affected. Pathophysiology As the name suggests, a person with this syndrome has one Y chromosome and four X chromosomes on the 23rd pair, resulting in forty-nine chromosomes instead of the usual forty-six. Like most aneuploidy disorders, 49,XXXXY syndrome is often associated with intellectual disability. It can be considered a variant of Klinefelter syndrome (47,XXY). Individuals with this syndrome are typically mosaic, being 49,XXXXY/48, XXXX. It is genetic but not hereditary, meaning that although the parents' genes cause the syndrome, the likelihood of having more than one child with the syndrome is low. The chance of inheriting the disorder is about one percent. Diagnosis 49,XXXXY can be clinically diagnosed through karyotyping. Facial dysmorphia and other somatic abnormalities may prompt genetic testing. Treatment While there is no treatment to correct the genetic anomaly of this syndrome, its symptoms can be managed. Due to infertility, one man from Iran used artificial reproductive techniques. An infant in Iran diagnosed with 49,XXXXY syndrome was born with patent ductus arteriosus, which was corrected surgically, and other complications that were addressed with replacement therapy. Testosterone therapy has been shown to enhance motor skills, speech, and nonverbal IQ in males with 49,XXXXY.

Inflammatory bowel disease, or IBD, refers to a group of disorders that lead to inflammation and swelling of the digestive tract tissues. The most prevalent forms of IBD are: Ulcerative colitis. This condition causes inflammation and ulcers along the colon and rectum lining. Crohn's disease. This type of IBD involves inflammation of the digestive tract lining, often affecting the deeper layers. It typically impacts the small intestine but can also affect the large intestine and, less commonly, the upper gastrointestinal tract. Symptoms of both ulcerative colitis and Crohn's disease often include abdominal pain, diarrhea, rectal bleeding, severe fatigue, and weight loss. For some, IBD is a mild condition, while for others, it can cause disability and lead to life-threatening complications. Symptoms Symptoms of inflammatory bowel disease vary based on the severity and location of inflammation. They can range from mild to severe, with periods of active illness followed by remission. Common symptoms of both Crohn's disease and ulcerative colitis include: Diarrhea. Abdominal pain and cramping. Blood in the stool. Loss of appetite. Unintentional weight loss. Extreme fatigue. When to see a doctor Consult a healthcare professional if you notice a persistent change in bowel habits or experience any symptoms of inflammatory bowel disease. Although IBD is not typically fatal, it is a serious condition that can lead to life-threatening complications in some individuals. Causes The precise cause of inflammatory bowel disease is unknown. While diet and stress were once suspected, they are now understood to potentially worsen IBD but not cause it. Several factors likely contribute to its development. Immune system. A possible cause involves changes in immune system function. When the immune system attempts to combat an invading virus or bacterium, an atypical immune response may lead to an attack on the digestive tract cells. Genes. Various genetic markers are linked to IBD. Family traits also seem to play a role, as IBD is more common in individuals with family members who have the disease. However, most IBD sufferers do not have a family history of the condition. Environmental triggers. Researchers believe environmental factors may contribute to the development of IBD, especially those affecting the gut microbiome. These may include: Growing up in a sterile environment with limited germ exposure. Experiencing a gastrointestinal infection early in life. Taking antibiotics during the first year of life. Primarily being bottle-fed. Risk factors Risk factors for inflammatory bowel disease include: Age. Most people are diagnosed with IBD before age 30, but some may not develop the disease until their 50s or 60s. Race or ethnicity. IBD is more prevalent among white individuals but can occur in anyone. The incidence is also rising in other racial and ethnic groups. Family history. Having a blood relative with the disease, such as a parent, sibling, or child, increases your risk. Cigarette smoking. Smoking is the most significant controllable risk factor for Crohn's disease. Although smoking might help prevent ulcerative colitis, its overall health risks outweigh any benefits. Quitting smoking can enhance digestive tract health and offer numerous other health benefits. Nonsteroidal anti-inflammatory medicines. These include ibuprofen (Advil, Motrin IB, others), naproxen sodium (Aleve), diclofenac sodium, and others. These medicines may increase the risk of developing IBD or worsen the disease in those already affected. Complications Ulcerative colitis and Crohn's disease share some complications, while others are unique to each condition. Common complications include: Colon cancer. Having ulcerative colitis or Crohn's disease that affects most of the colon increases the risk of colon cancer. Regular colonoscopy screenings typically begin 8 to 10 years after diagnosis. Consult a healthcare professional about when and how often to undergo this test. Skin, eye, and joint inflammation. Conditions such as arthritis, skin lesions, and eye inflammation (uveitis) may occur during IBD flare-ups. Medicine side effects. Some IBD medications carry infection risks and a small chance of certain cancers. Corticosteroids may be linked to osteoporosis, high blood pressure, and other conditions. Primary sclerosing cholangitis. In this rare condition associated with IBD, inflammation leads to scarring in the bile ducts, narrowing them and restricting bile flow, potentially causing liver damage. Blood clots. IBD increases the risk of blood clots in veins and arteries. Severe dehydration. Excessive diarrhea can lead to dehydration. Crohn's disease complications may include: Bowel obstruction. Crohn's disease affects the entire bowel wall thickness, leading to thickening and narrowing, which may block digestive content flow. Surgery might be necessary to remove the affected bowel section. Rarely, bowel or colon obstruction can occur in ulcerative colitis and may indicate colon cancer. Malnutrition. Diarrhea, abdominal pain, and cramping can hinder eating or nutrient absorption, leading to malnutrition. Anemia, due to low iron or vitamin B-12, is also common. Fistulas. Inflammation can extend through the intestinal wall, creating a fistula, an abnormal connection between body parts. Fistulas near the anal area are most common but can also occur internally or in the abdominal wall. An infected fistula may form an abscess. Anal fissure. A small tear in the tissue lining the anus or surrounding skin, often causing painful bowel movements and potentially leading to an anal fistula. Ulcerative colitis complications may include: Toxic megacolon. Ulcerative colitis can cause rapid colon enlargement and swelling, a serious condition known as toxic megacolon. Perforated colon. A perforated colon is most often caused by toxic megacolon but can also occur independently.

Irritable bowel syndrome (IBS) is a prevalent condition impacting the stomach and intestines, also known as the gastrointestinal tract. Symptoms include cramping, abdominal pain, bloating, gas, and either diarrhea or constipation, or both. IBS is a chronic condition requiring long-term management. Only a small portion of individuals with IBS experience severe symptoms. Some can manage their symptoms through diet, lifestyle, and stress management. More severe symptoms may require medication and counseling. IBS does not lead to changes in bowel tissue or increase the risk of colorectal cancer. Symptoms IBS symptoms vary but are typically long-lasting. The most common include: Abdominal pain, cramping, or bloating associated with bowel movements. Alterations in stool appearance. Changes in stool frequency. Other frequently related symptoms include a feeling of incomplete evacuation and increased gas or mucus in the stool. When to see a doctor Consult a healthcare professional if you experience a persistent change in bowel habits or other IBS symptoms. They might indicate a more serious condition, such as colon cancer. More serious symptoms include: Weight loss. Nighttime diarrhea. Rectal bleeding. Iron deficiency anemia. Unexplained vomiting. Pain not relieved by passing gas or stool. Causes The precise cause of IBS is unknown. Factors that may contribute include: Muscle contractions in the intestine. The intestinal walls are lined with muscle layers that contract as food moves through the digestive tract. Stronger, longer-lasting contractions can cause gas, bloating, and diarrhea. Weak contractions can slow food passage, leading to hard, dry stools. Nervous system. Problems with digestive system nerves may cause discomfort when the abdomen stretches from gas or stool. Poorly coordinated signals between the brain and intestines can cause the body to overreact to normal digestive process changes, resulting in pain, diarrhea, or constipation. Severe infection. IBS can develop after a severe diarrhea episode caused by bacteria or a virus, known as gastroenteritis. IBS might also be linked to bacterial overgrowth in the intestines. Early-life stress. Individuals exposed to stressful events, particularly in childhood, tend to experience more IBS symptoms. Changes in gut microbes. This includes changes in bacteria, fungi, and viruses that typically reside in the intestines and are crucial for health. Research suggests that the microbes in people with IBS differ from those without IBS. Triggers IBS symptoms can be triggered by: Food. The role of food allergy or intolerance in IBS isn't fully understood. A true food allergy rarely causes IBS. However, many people experience worsened IBS symptoms after consuming certain foods or beverages, such as wheat, dairy products, citrus fruits, beans, cabbage, milk, and carbonated drinks. Stress. Most individuals with IBS experience worsened or more frequent symptoms during periods of increased stress. While stress may exacerbate symptoms, it doesn't cause them. Risk factors Many people occasionally experience IBS symptoms. However, you are more likely to have the syndrome if you: Are young. IBS is more common in individuals under 50. Are female. In the United States, IBS is more prevalent among women. Estrogen therapy before or after menopause is also a risk factor for IBS. Have a family history of IBS. Genetics may play a role, as might shared environmental factors or a combination of genetics and environment. Have anxiety, depression, or other mental health issues. A history of sexual, physical, or emotional abuse might also be a risk factor. Complications Chronic constipation or diarrhea can lead to hemorrhoids. Additionally, IBS is associated with: Poor quality of life. Many individuals with moderate to severe IBS report a diminished quality of life. Research shows that those with IBS miss work three times more often than those without bowel symptoms. Mood disorders. Experiencing IBS symptoms can lead to depression or anxiety, which can also exacerbate IBS.

XX male syndrome , also referred to as de la Chapelle syndrome or 46,XX testicular disorder of sex development (46,XX DSD), is a rare condition where an individual with a 46,XX karyotype develops a male phenotype . In 90% of these cases, the syndrome results from the Y chromosome 's SRY gene, which initiates male reproductive development, being unusually incorporated during the crossing over of genetic material that occurs between the pseudoautosomal regions of the X and Y chromosomes during meiosis in the father. When the X chromosome carrying the SRY gene merges with a normal X from the mother during fertilization , it leads to testicular differentiation of the gonads. Less frequently, SRY -negative individuals, who generally have a typical female karyotype, may experience this condition due to a mutation in an  autosomal  or X chromosomal gene. The degree of masculinization in affected individuals varies, and they are infertile. This syndrome is identified in about 1 in 20,000 newborn boys, making it much rarer than  Klinefelter syndrome . Medical treatment varies, though it is often unnecessary. The clinical term "de la Chapelle syndrome" honors Finnish scientist Albert de la Chapelle, who first described it. Signs and symptoms Although variability exists, most individuals diagnosed with de la Chapelle Syndrome exhibit a typical male phenotype, with male-typical external genitalia, making early diagnosis rare. Genital ambiguity is more frequent in those lacking the SRY gene or other Y chromosome-derived genes, though reported rates vary. Such ambiguities may include hypospadias , micropenis , and cryptorchidism. In most SRY-positive men, significant signs are few before puberty, although small testes are almost universally observed; post-puberty, gynecomastia often develops. XX males tend to be shorter on average than XY males. Based on limited evidence, most have typical body and pubic hair, penis size, libido, and erectile function. All reported cases show sterility, with azoospermia (absence of sperm in the ejaculate). Due to its subtle presentation, many are diagnosed late when seeking infertility treatment in adulthood; it's probable that many cases remain undiagnosed. Masculinization The extent to which individuals with XX male syndrome develop a male phenotype varies, even among SRY-positive individuals. Masculinization in SRY-positive XX males is believed to depend on which X chromosome is inactivated. Typical XX females undergo X inactivation , where one X chromosome is silenced. It is thought that X inactivation in XX males may explain the genital ambiguities and incomplete masculinization seen in SRY-positive XX males. The X chromosome with the SRY gene is preferentially active 90% of the time, explaining the complete male phenotype often observed in SRY-positive cases. In the remaining 10%, the X chromosome with the SRY gene is inactivated, leading to incomplete masculinization. Masculinization in SRY-negative individuals depends on which genes have mutations and when these mutations occur during development. Genetics Males typically possess one X and one Y chromosome in each diploid cell, while females usually have two X chromosomes. SRY-positive XX males have two X chromosomes, with one carrying genetic material (the SRY gene ) from the Y chromosome, causing them to develop a male phenotype despite having chromosomes more typical of females. Some 46,XX individuals lack the SRY gene (SRY-negative); the reason for their male phenotype is not well understood and remains under research. SRY-positive The SRY gene, typically found on the Y chromosome, is crucial in sex determination by initiating testicular development. In about 80% of XX males, the SRY gene is present on one of the X chromosomes. The condition arises from an abnormal genetic material exchange between chromosomes (translocation). This exchange happens randomly during sperm cell formation in the affected person's father. The Y chromosome's tip contains the SRY gene, and during recombination , a translocation occurs where the SRY gene becomes part of the X chromosome. If a fetus is conceived from a sperm cell with an X chromosome carrying the SRY gene, it develops as a male despite lacking the full Y chromosome. This form is known as SRY-positive 46,XX testicular disorder of sex development. SRY-negative About 20% of those with 46 XX testicular disorder of sex development lack the SRY gene . This form is termed SRY-negative 46,XX testicular disorder of sex development. The disorder's cause in these individuals is often unknown, though changes affecting other genes have been identified. SRY-negative individuals are more likely to have ambiguous genitalia than those with the SRY-positive form. The exact cause remains unknown, but three theories exist: first, undetected gonadal mosaicism for SRY; second, de-repression of male development due to mutations in non-Y chromosome genes; third, altered expression of other genes downstream of SRY, leading to masculinization. For instance, mutations in the SOX9 gene may contribute, as SOX9 is involved in testes differentiation. Another proposed cause is mutations to the DAX1 gene, which may suppress masculinization; if there is a loss of function of DAX1, testes can develop in an XX individual. Mutations in SF1 and WNT4 genes have also been studied as potential causes. Diagnosis No consensus exists on diagnostic criteria; diagnosis typically involves evaluating physical development alongside karyotyping and the presence of the SRY gene or related genes, such as SOX9. Hormone level tests and azoospermia assessments may also be conducted. Most individuals with de la Chapelle Syndrome have a typical male phenotype at birth, so diagnosis usually occurs at puberty onset, if traits like gynecomastia are investigated, or later, when infertility is explored. Diagnosis at birth is more common in SRY-negative individuals, who are more likely to have ambiguous genitalia. When evaluating ambiguous genitalia, such as a small phallus, hypospadias , or labioscrotal folds, exploratory surgery may determine the presence of male and/or female internal genitalia. Indicators include two testes that haven't descended the inguinal canal , though this is seen in a minority of XX males, and the absence of Müllerian tissue . External indicators include decreased body weight, gynecomastia, and small testes. A standard karyotype can be performed to cytogenetically confirm that an individual with a partial or complete male phenotype has an XX genotype. The presence and location of the SRY gene can be determined using fluorescence in situ hybridization ( FISH ). Treatment Treatment generally focuses on affirming the gender presentation of affected men, varies significantly based on the individual's phenotype, and may include counseling. In some XX males, testosterone therapy may enhance virilization. While most XX males have typical male external genital development, cases of genital ambiguity may be addressed with hormonal therapy, surgery, or both. Gonadal surgery may be performed to remove partial or whole female genitalia, followed by plastic and reconstructive surgery to create a more externally male appearance. Conversely, the individual may prefer a more feminine appearance, and feminizing genitoplasty can make the ambiguous genitalia appear more female. There is no treatment for infertility in XX males – supportive management and options like sperm donation or adoption are advised. Epidemiology It is estimated that 1 in every 20,000 to 30,000 males has a 46,XX karyotype, making it much rarer than other related syndromes, such as Klinefelter syndrome .

Estradiol is a form of estrogen, a hormone that plays a crucial role in the development and regulation of the female reproductive system and secondary sexual characteristics. It is primarily produced in the ovaries, but also in smaller amounts by the adrenal glands and fat tissues. Estradiol is essential for various physiological processes in both women and men, although it is most commonly associated with female health. Biological function The emergence of secondary sex characteristics in women is influenced by estrogens, particularly estradiol. These changes begin at puberty, are most prominent during the reproductive years, and diminish with reduced estradiol levels after menopause. Estradiol leads to breast development, and alters body shape, affecting bones, joints, and fat distribution. In females, estradiol causes breast development, hip widening, a feminine fat distribution (with fat primarily in the breasts, hips, thighs, and buttocks), and the maturation of the vagina and vulva. It also influences the pubertal growth spurt (indirectly through increased growth hormone secretion) and epiphyseal closure (thereby affecting final height) in both sexes. Reproduction Female reproductive system In females, estradiol functions as a growth hormone for reproductive organ tissues, maintaining the lining of the vagina, cervical glands, endometrium, and the fallopian tube lining. It promotes the growth of the myometrium. Estradiol is essential for sustaining oocytes in the ovary. Throughout the menstrual cycle, estradiol produced by developing follicles initiates, through a positive feedback loop, the hypothalamic-pituitary events that result in the luteinizing hormone surge, triggering ovulation. In the luteal phase, estradiol, along with progesterone, readies the endometrium for implantation. During pregnancy, estradiol levels rise due to placental production. The role of estradiol, together with estrone and estriol, in pregnancy is not entirely understood. They may enhance uterine blood flow, myometrial growth, stimulate breast development, and at term, aid in cervical softening and the expression of myometrial oxytocin receptors. In baboons, inhibiting estrogen production results in pregnancy loss, indicating estradiol's role in maintaining pregnancy. Research is exploring the role of estrogens in initiating labor. Estradiol's actions are necessary prior to progesterone exposure in the luteal phase. Skeletal system Estradiol significantly influences bone health. Those lacking it (or other estrogens) tend to grow tall and eunuchoid, as epiphyseal closure is delayed or may not occur. Bone density is also impacted, leading to early osteopenia and osteoporosis. Low estradiol levels might also indicate a higher risk of fractures, with post-menopausal women experiencing the most frequent bone fractures. Women after menopause face a rapid decrease in bone mass due to a relative lack of estrogen. Skin health Both the estrogen receptor and the progesterone receptor have been identified in the skin, including in keratinocytes and fibroblasts. During menopause and beyond, lower levels of female sex hormones lead to atrophy, thinning, and more pronounced wrinkling of the skin, along with a decrease in skin elasticity, firmness, and strength. These changes accelerate skin aging and are due to reduced collagen content, irregularities in the morphology of epidermal skin cells, decreased ground substance between skin fibers, and reduced capillaries and blood flow. Additionally, the skin becomes more dry during menopause due to diminished skin hydration and surface lipids (sebum production). Alongside chronological aging and photoaging, estrogen deficiency during menopause is one of the three primary factors influencing skin aging. Hormone replacement therapy, involving systemic treatment with estrogen alone or combined with a progestogen, offers well-documented and significant benefits for the skin of postmenopausal women. These benefits include increased skin collagen content, thickness, elasticity, hydration, and surface lipids. Topical estrogen has shown similar positive effects on the skin. Furthermore, a study found that topical 2% progesterone cream significantly enhances skin elasticity and firmness and noticeably reduces wrinkles in peri- and postmenopausal women. However, skin hydration and surface lipids did not significantly change with topical progesterone. These findings imply that progesterone, like estrogen, also offers beneficial effects on the skin and may independently protect against skin aging. Nervous system Estrogens can be synthesized in the brain from steroid precursors. Acting as antioxidants, they have demonstrated neuroprotective properties. The positive and negative feedback loops of the menstrual cycle involve ovarian estradiol, which connects to the hypothalamic-pituitary system to regulate gonadotropins. Estrogen is believed to have a crucial impact on women's mental health, with suggested links between hormone levels, mood, and well-being. Sharp decreases, fluctuations, or prolonged low levels of estrogen may be associated with significant mood drops. Clinical recovery from depression postpartum, perimenopause, and postmenopause has been shown to be effective once estrogen levels are stabilized and/or restored. Estrogen has been found to enhance the secretion of oxytocin and to increase the expression of its receptor, the oxytocin receptor, in the brain. In women, a single dose of estradiol has been found to be enough to raise circulating oxytocin levels. Gynecological cancers Estradiol has been linked to the development and progression of cancers such as breast cancer, ovarian cancer, and endometrial cancer. It influences target tissues primarily by interacting with two nuclear receptors known as estrogen receptor α (ERα) and estrogen receptor β (ERβ). These estrogen receptors play a role in modulating gene expression. When estradiol binds to the ERs, the receptor complexes attach to specific DNA sequences, potentially causing DNA damage and increasing cell division and DNA replication. Eukaryotic cells respond to DNA damage by either stimulating or inhibiting the G1, S, or G2 phases of the cell cycle to initiate DNA repair. Consequently, this leads to cellular transformation and cancer cell proliferation. Cardiovascular system Estrogen has an impact on specific blood vessels. Enhanced arterial blood flow has been observed in coronary arteries. 17-beta-estradiol (E2) is regarded as the most potent estrogen present in humans. E2 affects vascular function, apoptosis, and damage during cardiac ischemia and reperfusion. E2 can shield the heart and individual cardiac myocytes from ischemia-related injuries. Following a heart attack or prolonged hypertension, E2 prevents the harmful effects of pathological heart remodeling During pregnancy, elevated levels of estrogens, particularly estradiol, increase coagulation and the risk of venous thromboembolism. Other functions Estradiol has intricate effects on the liver. It influences the production of various proteins, such as lipoproteins, binding proteins, and proteins involved in blood clotting. In elevated levels, estradiol can cause cholestasis, such as cholestasis of pregnancy. Certain gynecological conditions rely on estrogen, including endometriosis, leiomyomata uteri, and uterine bleeding. Biological activity Estradiol primarily functions as an agonist of the estrogen receptor (ER), which is a nuclear steroid hormone receptor. The ER has two subtypes, ERα and ERβ, and estradiol effectively binds to and activates both. Activation of the ER leads to changes in gene transcription and expression in cells that express ER, which is the main way estradiol exerts its biological effects in the body. Estradiol also acts as an agonist of membrane estrogen receptors (mERs), like GPER (GPR30), a newly identified non-nuclear receptor for estradiol, through which it can produce various rapid, non-genomic effects. Unlike ER, GPER seems to be selective for estradiol and has very low affinities for other natural estrogens like estrone and estriol. Other mERs besides GPER include ER-X, ERx, and Gq-mER. ERα/ERβ are initially inactive, trapped in multimolecular chaperone complexes centered around heat shock protein 90 (HSP90), containing p23 protein and immunophilin, and are mostly located in the cytoplasm and partially in the nucleus. In the E2 classical pathway, or estrogen classical pathway, estradiol enters the cytoplasm, where it binds to ERs. Once estradiol is bound, ERs detach from the chaperone complexes, allowing them to dimerize, move to the nucleus, and bind to specific DNA sequences (estrogen response element, ERE), facilitating gene transcription that can occur over hours and days. When administered by subcutaneous injection in mice, estradiol is approximately 10 times more potent than estrone and about 100 times more potent than estriol. Therefore, estradiol is the primary estrogen in the body, although the roles of estrone and estriol as estrogens are considered significant. Biosynthesis Estradiol, similar to other steroid hormones, originates from cholesterol. Following side chain cleavage and utilizing either the Δ5 or Δ4- pathway, androstenedione serves as the primary intermediary. Some of the androstenedione is transformed into testosterone, which is then converted to estradiol by aromatase. Alternatively, androstenedione can be aromatized into estrone, which is subsequently converted to estradiol via 17β-hydroxysteroid dehydrogenase (17β-HSD). During the reproductive years, the majority of estradiol in women is synthesized by the granulosa cells of the ovaries through the aromatization of androstenedione (produced in the theca folliculi cells) to estrone, which is then converted to estradiol by 17β-HSD. Smaller quantities of estradiol are also produced by the adrenal cortex, and in men, by the testes. Estradiol is not exclusively produced in the gonads; notably, fat cells generate active precursors to estradiol, continuing even after menopause. Estradiol is also synthesized in the brain and within arterial walls. Distribution In plasma, estradiol is primarily bound to SHBG and albumin. Only about 2.21% (± 0.04%) of estradiol is free and biologically active, with this percentage remaining stable throughout the menstrual cycle. The inactivation of estradiol involves its conversion to less-active estrogens, such as estrone and estriol. Estriol is the main urinary metabolite. Estradiol is conjugated in the liver to form estrogen conjugates like estradiol sulfate and estradiol glucuronide, which are excreted via the kidneys. Some water-soluble conjugates are excreted through the bile duct and partially reabsorbed after hydrolysis from the intestinal tract. This enterohepatic circulation helps maintain estradiol levels. Estradiol is also metabolized by hydroxylation into catechol estrogens. In the liver, it undergoes non-specific metabolism by CYP1A2, CYP3A4, and CYP2C9 through 2-hydroxylation into 2-hydroxyestradiol, and by CYP2C9, CYP2C19, and CYP2C8 through 17β-hydroxy dehydrogenation into estrone, with other cytochrome P450 (CYP) enzymes and metabolic transformations also playing a role. Estradiol is further conjugated with an ester into lipoidal estradiol forms such as estradiol palmitate and estradiol stearate to some degree; these esters are stored in adipose tissue and may serve as a long-term reservoir of estradiol. Excretion Estradiol is excreted as glucuronide and sulfate estrogen conjugates in urine. After an intravenous injection of labeled estradiol in women, nearly 90% is excreted in urine and feces within 4 to 5 days. Enterohepatic recirculation delays the excretion of estradiol. Level Estradiol levels in premenopausal women vary significantly throughout the menstrual cycle, with reference ranges differing across sources. During the early to mid follicular phase (or the first week of the menstrual cycle, known as menses), estradiol levels are minimal, usually ranging from 20 to 80 pg/mL according to most laboratories. These levels gradually rise during the mid to late follicular phase (or the second week of the menstrual cycle) until the pre-ovulatory phase. During pre-ovulation (approximately 24 to 48 hours), estradiol levels peak, reaching their highest concentrations of the menstrual cycle. Typically, circulating levels range from 130 to 200 pg/mL, but in some women, they may reach 300 to 400 pg/mL, with some laboratories setting the upper limit of the reference range even higher (e.g., 750 pg/mL). After ovulation (mid-cycle) and during the luteal phase (the latter half of the menstrual cycle), estradiol levels stabilize, fluctuating between about 100 and 150 pg/mL during the early and mid luteal phase, and dropping to around 40 pg/mL in the late luteal phase, or a few days before menstruation. The mean integrated levels of estradiol over a full menstrual cycle have been reported by various sources as 80, 120, and 150 pg/mL. Although there are conflicting reports, one study found mean integrated estradiol levels of 150 pg/mL in younger women, whereas in older women, levels ranged from 50 to 120 pg/mL. During the reproductive years, estradiol levels in women are generally higher than those of estrone, except during the early follicular phase of the menstrual cycle. Thus, estradiol is considered the predominant estrogen in terms of absolute serum levels and estrogenic activity during these years. During pregnancy, estriol becomes the predominant circulating estrogen, and this is the only time estetrol is present in the body. In contrast, estrone predominates during menopause, based on serum levels. In men, estradiol, derived from testosterone , is present at serum levels comparable to those in postmenopausal women (14–55 versus <35 pg/mL, respectively). It has also been noted that in a comparison between 70-year-old men and women, estradiol levels are approximately 2- to 4-fold higher in men. Measurement In women, serum estradiol is measured in a clinical laboratory and primarily reflects ovarian activity. The Estradiol blood test quantifies estradiol in the blood, assessing the function of the ovaries, placenta, and adrenal glands. This test can identify baseline estrogen levels in women with amenorrhea or menstrual dysfunction, and detect hypoestrogenicity and menopause. Additionally, monitoring estrogen during fertility therapy helps assess follicular growth and treatment progress. Estrogen-producing tumors show persistently high levels of estradiol and other estrogens. In precocious puberty, estradiol levels are inappropriately elevated. Ranges Laboratory results should always be interpreted using the specific ranges provided by the laboratory conducting the test. Chemistry Estradiol is an estrane steroid.[82] It is also referred to as 17β-estradiol to differentiate it from 17α-estradiol, or as estra-1,3,5(10)-triene-3,17β-diol. It has two hydroxyl groups, one at the C3 position and another at the 17β position, along with three double bonds in the A ring. Due to these two hydroxyl groups, estradiol is often abbreviated as E2. Structurally related estrogens, estrone (E1), estriol (E3), and estetrol (E4), have one, three, and four hydroxyl groups, respectively. Neuropsychopharmacology Product insert information for commercial prescription estradiol indicates it may cause depression. In a randomized, double-blind, placebo-controlled study, estradiol demonstrated gender-specific effects on fairness sensitivity. Overall, when the division of a given amount of money was framed as either fair or unfair in a modified version of the ultimatum game, estradiol increased the acceptance rate of fair-framed proposals among men and decreased it among women. However, among the placebo group, "the mere belief of receiving estradiol treatment significantly increased the acceptance of unfair-framed offers in both sexes," suggesting that "environmental" factors influenced responses to these presentations of the ultimatum game. Availability of Estradiol Medication Forms of Estradiol Tablets Transdermal patches Topical gels and creams Injectable forms Pellets Vaginal rings and tablets Considerations Consult with a healthcare professional before starting estradiol. Discuss potential side effects and contraindications. Regular monitoring may be necessary during treatment.

Estetrol is a naturally occurring estrogen that is produced by the human fetal liver during pregnancy. It is a member of the estrane family of hormones and is recognized for its unique properties compared to other estrogens. Biological Function Estetrol plays a crucial role in maintaining pregnancy and supporting fetal development. It is involved in various physiological processes, including the regulation of uterine growth and the preparation of the maternal body for childbirth. Biological Activity Estetrol exhibits estrogenic activity, influencing various target tissues such as the uterus, breast, and bone. It binds to estrogen receptors, primarily ERα, to exert its effects on gene expression and cellular function. Tissue-Selective Effect Estetrol shows selective estrogenic, neutral or anti-estrogenic activities in certain cell types and tissues. In rodent models, estetrol has shown to elicit potent estrogenic activity on ovulation, brain, bone tissue, cardiovascular system, and uterus, associated with ovulation inhibition, prevention of bone demineralization, cardioprotective effects and maintenance of uterovaginal tissues, respectively. Data from preclinical studies also suggest that estetrol has anti-estrogenic like effects on the breast and a limited impact on normal or malignant breast tissue when used at therapeutic concentration. This property of estetrol is associated with antagonistic effects on breast cell proliferation, migration and invasion in the presence of estradiol. The molecular mechanisms of action driving its tissue-selective actions rely on a specific profile of ERα activation, uncoupling nuclear and membrane activation. In the liver, Estetrol has a neutral activity, which is reflected by a minimal impact on synthesis of hepatic coagulation factors, minimal impact on sex hormone-binding globulin (SHBG) synthesis and limited impact on lipid parameters, including triglycerides. Estetrol can therefore be described as the first Native Estrogen with Selective Tissue activity (NEST). Differences vs SERMs The selective tissue activity of estetrol is different from the effects of selective estrogen receptor modulators (SERMs), like tamoxifen and raloxifene. Estetrol, like SERMs, has selective tissue activity. However, SERMs interact with the ligand binding domain of ERα in a manner that is distinct from that of estrogens, including estetrol. Estetrol recruits the same co-regulators as other estrogens, while SERMs recruit other co-regulators. ERα Activation Estrogens can elicit their effects via nuclear ERα and/or membrane ERα signaling pathways. Estetrol presents a distinctive mode of action in terms of ERα activation. Like other estrogens, estetrol binds to, and activates the nuclear ERα to induce gene transcription. However, estetrol induces very limited activity via membrane ERα in several tissues (e.g. in the breast) and antagonizes this pathway in the presence of estradiol, thereby uniquely uncoupling nuclear and membrane activation. Biosynthesis In the fetal liver , estetrol is synthesized from estradiol (E2) and estriol (E3) by two fetal liver enzymes , 15α- and 16α-hydroxylase, through hydroxylation. Estetrol can be detected in maternal urine from the 9th week of gestation. After birth, the neonatal liver rapidly loses its capacity to synthesize estetrol. During the second trimester of pregnancy, high levels of estetrol can be found in maternal plasma, with steadily rising concentrations of unconjugated estetrol to about 1 ng/mL (>3 nM) towards the end of pregnancy. Fetal plasma levels have been reported to be over 10 times higher than maternal plasma levels at parturition. Distribution In terms of plasma protein binding , estetrol displays moderate binding to albumin , and shows no binding to SHBG. The overall low plasma protein binding results in a ~50% free active fraction. This compares to a 1% active form for EE and ~2% for estradiol. Estetrol is equally distributed between red blood cells and plasma. Metabolism Cytochrome P450 (CYP) enzymes do not play a major role in the metabolism of estetrol. Instead, estetrol undergoes extensive phase 2 metabolism in the liver to form glucuronide and sulphate conjugates. The two main metabolites, estetrol-3-glucuronide and estetrol-16-glucuronide, have negligible estrogenic activity. Excretion Estetrol is mainly excreted in urine . Estetrol is an end-stage product of metabolism, which is not converted back into active metabolites like estriol, estradiol or estrone. Estetrol Medication is Available in Estetrol (as monohydrate) 15 mg and drospirenone 3 mg Nextstellis (CA, US and Australia) – combined oral contraception. Estetrol (as monohydrate) 15 mg and drospirenone 3 mg Drovelis (EU) – combined oral contraception. Estetrol (as monohydrate) 15 mg and drospirenone 3 mg Lydisilka (EU) – combined oral contraception. Considerations Consult with a healthcare professional before starting estetrol. Discuss potential side effects and contraindications. Regular monitoring may be necessary during treatment.

Estriol is one of the three main estrogens produced by the human body, the others being estradiol and estrone. It is primarily produced during pregnancy by the placenta and is considered a weak estrogen compared to the other two forms. Estriol plays a significant role in various physiological processes, particularly during the menstrual cycle and pregnancy. Biological activity Estriol is an estrogen and acts as an agonist at the estrogen receptors ERα and ERβ. It is significantly less potent than estradiol, making it a relatively weak estrogen. One in vitro study found that the relative binding affinity (RBA) of estriol for human ERα and ERβ was 11.3% and 17.6% of that of estradiol, respectively, and its relative transactivational capacity at ERα and ERβ was 10.6% and 16.6% of that of estradiol, respectively. Another in vitro study, however, reported the RBA of estriol for ERα and ERβ as 14% and 21% of those of estradiol, respectively, suggesting that unlike estradiol and estrone, estriol might have a preferential affinity for ERβ. While estriol is an effective agonist of the ERs, it is noted to have mixed agonist–antagonist (partial agonist) activity at the ER. Alone, it exhibits weak estrogenic effects, but in the presence of estradiol, it acts as an antiestrogen. In mice, when administered via subcutaneous injection, estradiol is approximately 10 times more potent than estrone and about 100 times more potent than estriol. Unlike estriol, estrone can be converted into estradiol, and its potency in vivo is largely due to this conversion. Besides being an agonist of the nuclear ERs, at high concentrations (around 1,000–10,000 nM), estriol also acts as an antagonist of the GPER, a membrane estrogen receptor, where estradiol acts as an agonist. Estradiol promotes breast cancer cell growth via GPER (in addition to the ER), while estriol has been shown to inhibit estradiol-induced proliferation of triple-negative breast cancer cells by blocking the GPER. Estriol plays a significant role in both the menstrual cycle and pregnancy, supporting reproductive health and fetal development, making it an essential hormone in women's health. Biosynthesis In non-pregnant women , estriol is produced in minimal amounts, making circulating levels almost undetectable. Unlike estradiol and estrone, estriol is not synthesized or secreted by the ovaries but is primarily derived from the 16α-hydroxylation of estradiol and estrone by cytochrome P450 enzymes (e.g., CYP3A4), mainly in the liver. In non-pregnant women, estriol is rapidly cleared from the circulation, resulting in very low circulating levels, although its concentration in urine is relatively high. Even though estriol levels in the bloodstream are very low outside of pregnancy, parous women have been found to have somewhat higher levels of estriol compared to nulliparous women. In pregnant women, Estriol is produced in quantities that are notable only during pregnancy. Levels of estriol increase 1,000-fold during pregnancy, whereas levels of estradiol and estrone increase 100-fold, and estriol accounts for 90% of the estrogens in the urine of pregnant women. At term, the daily production of estriol by the placenta is 35 to 45 mg, and levels in the maternal circulation are 8 to 13 ng/dL. The placenta produces pregnenolone and progesterone from circulating cholesterol . Pregnenolone is taken up by the fetal adrenal glands and converted into dehydroepiandrosterone (DHEA), which is then sulfated by steroid sulfotransferase into dehydroepiandrosterone sulfate (DHEA-S). DHEA-S is hydroxylated by high CYP3A7 expression and activity into 16α-hydroxy-DHEA-S (16α-OH-DHEA-S) in the fetal liver and to a limited extent in the fetal adrenal glands. 16α-OH-DHEA-S is then taken up by the placenta. Due to high expression of steroid sulfatase in the placenta, 16α-OH-DHEA-S is rapidly cleaved into 16α-OH-DHEA . Then, 16α-OH-DHEA is converted by 3β-hydroxysteroid dehydrogenase type I (3β-HSD1) into 16α-hydroxyandrostenedione (16α-OH-A4) and 16α-OH-A4 is converted by aromatase into 16α-hydroxyestrone (16α-OH-E1), which is subsequently converted into estriol by 17β-hydroxysteroid dehydrogenase and then secreted predominantly into the maternal circulation. Approximately 90% of precursors in estriol formation originate from the fetus. During pregnancy, 90 to 95% of estriol in the maternal circulation is conjugated in the form of estriol glucuronide and estriol sulfate , and levels of unconjugated estriol are slightly less than those of unconjugated estradiol and similar to those of unconjugated estrone. As such, target tissues are likely to be exposed to similar amounts of free estriol, estradiol, and estrone during pregnancy. Estrone and estradiol are also produced in the placenta during pregnancy. However, in the case of estrone and estradiol, DHEA-S is taken up by the placenta and cleaved by steroid sulfatase into dehydroepiandrosterone (DHEA), DHEA is converted by 3β-hydroxysteroid dehydrogenase type I into androstenedione , and androstenedione is aromatized into estrone. Then, placental 17β-hydroxysteroid dehydrogenase interconverts estrone and estradiol and the two hormones are secreted into the maternal circulation. DHEA-S that is taken up by the placenta is mainly produced by the fetal adrenal glands. Distribution Estriol has a low binding affinity to sex hormone-binding globulin (SHBG) compared to estradiol, resulting in a larger portion being available for biological activity. Metabolism Estriol undergoes metabolism through glucuronidation and sulfation. Excretion The primary urinary metabolites of exogenous estriol administered through intravenous injection in baboons have been identified as estriol 16α-glucuronide (65.8%), estriol 3-glucuronide (14.2%), estriol 3-sulfate (13.4%), and estriol 3-sulfate 16α-glucuronide (5.1%). The metabolism and excretion of estriol in these animals closely resemble what is observed in humans. In non-pregnant women, urinary excretion of estriol ranges from 0.02–0.1 mg every 24 hours. In contrast, in near-term pregnant women, urinary excretion of estriol ranges from 50–150 mg every 24 hours. Chemistry Estriol, also referred to as 16α-hydroxyestradiol or estra-1,3,5(10)-triene-3,16α,17β-triol, is a naturally occurring estrane steroid characterized by double bonds between the C1 and C2, C3 and C4, and C5 and C10 positions, along with hydroxyl groups at the C3, C16α, and C17β positions. The term estriol and its abbreviation E3 originate from the chemical terms estr in (estra-1,3,5(10)-triene) and triol (indicating three hydroxyl groups). Availability of Estriol Medication Estriol medication can be found in various forms and formulations. Here are some common options: Oral Tablets: Estriol is available in tablet form for oral administration. Topical Creams: Estriol is often formulated as a cream for topical application. Vaginal Suppositories: Estriol can be found in suppository form for vaginal use. Injectable Forms: In some cases, estriol may be available as an injectable medication. Considerations Consult with a healthcare professional before starting estriol. Discuss potential side effects and contraindications. Regular monitoring may be necessary during treatment.