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Androgen insensitivity syndrome

Androgen insensitivity syndrome (AIS) is a condition involving the inability to respond to androgens, typically due to androgen receptor dysfunction.

It affects 1 in 20,000 to 64,000 XY (karyotypically male) births. The condition results in the partial or complete inability of cells to respond to androgens. This unresponsiveness can impair or prevent the development of male genitals, as well as impairing or preventing the development of male secondary sexual characteristics at puberty. It does not significantly impair female genital or sexual development. The insensitivity to androgens is therefore clinically significant only when it occurs in genetic males, (i.e. individuals with a Y-chromosome, or more specifically, an SRY gene). Clinical phenotypes in these individuals range from a typical male habitus with mild spermatogenic defect or reduced secondary terminal hair, to a full female habitus, despite the presence of a Y-chromosome.

AIS is divided into three categories that are differentiated by the degree of genital masculinization:
 * Mild androgen insensitivity syndrome (MAIS) is indicated when the external genitalia are those of a typical 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 are those of a typical female (a vulva)

Androgen insensitivity syndrome is the largest single entity that leads to 46,XY undermasculinized genitalia.

Management of AIS is currently limited to symptomatic management; no method is currently available to correct the malfunctioning androgen receptor proteins produced by AR gene mutations. Areas of management include sex assignment, genitoplasty, gonadectomy to reduce 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 approximately 2,757 nucleotides (919 codons) spanning eight exons, designated 1-8 or A-H. Introns vary in size between 0.7 and 26 kb. Like other nuclear receptors, the AR protein consists of several functional domains: the transactivation domain (also called the transcription-regulation domain or the amino / NH2-terminal domain), the DNA-binding domain, the hinge region, and the steroid-binding domain (also called the carboxyl-terminal ligand-binding domain). The transactivation domain is encoded by exon 1, and makes up more than half of the AR protein. Exons 2 and 3 encode the DNA-binding domain, while the 5' portion of exon 4 encodes the hinge region. The remainder of exons 4 through 8 encodes the ligand binding domain.

Trinucleotide satellite lengths and AR transcriptional activity
The AR gene contains two polymorphic trinucleotide microsatellites in exon 1. The first microsatellite (nearest the 5' end) contains 8 to 60 repetitions of the glutamine codon "CAG" and is thus known as the polyglutamine tract. The second microsatellite contains 4 to 31 repetitions of the glycine codon "GGC" and is known as the polyglycine tract. The average number of repetitions varies by ethnicity, with Caucasians exhibiting an average of 21 CAG repeats, and Blacks 18. In men, disease states are associated with extremes in polyglutamine tract length; prostate cancer, hepatocellular carcinoma, and intellectual disability are associated with too few repetitions, while spinal and bulbar muscular atrophy (SBMA) is associated with a CAG repetition length of 40 or more. Some studies indicate that the length of the polyglutamine tract is inversely correlated with transcriptional activity in the AR protein, and that longer polyglutamine tracts may be associated with male infertility  and undermasculinized genitalia in men. However, other studies have indicated no such correlation exists. A comprehensive meta-analysis of the subject published in 2007 supports the existence of the correlation, and concluded these discrepancies could be resolved when sample size and study design are taken into account. Some studies suggest longer polyglycine tract lengths are also associated with genital masculinization defects in men. Other studies find no such association.

AR mutations
As of 2010, over 400 AR mutations have been reported in the AR mutation database, and the number continues to grow. Inheritance is typically maternal and follows an X-linked recessive pattern; individuals with a 46,XY karyotype always express the mutant gene since they have only one X chromosome, whereas 46,XX carriers are minimally affected. About 30% of the time, the AR mutation is a spontaneous result, and is not inherited. Such de novo mutations are the result of a germ cell mutation or germ cell mosaicism in the gonads of one of the parents, or a mutation in the fertilized egg itself. In one study, three of eight de novo mutations occurred in the postzygotic stage, leading to the estimate that up to one-third of de novo mutations result in somatic mosaicism. Not every mutation of the AR gene results in androgen insensitivity; one particular mutation occurs in 8 to 14% of genetic males,   and is thought to adversely affect only a small number of individuals when other genetic factors are present.

Other causes
Some individuals with CAIS or PAIS do not have any AR mutations despite clinical, hormonal, and histological features sufficient to warrant an AIS diagnosis; up to 5% of women with CAIS do not have an AR mutation, as well as between 27 and 72% of individuals with PAIS.

In one patient, the underlying cause for presumptive PAIS was a mutant steroidogenic factor-1 (SF-1) protein. In another patient, CAIS was the result of a deficit in the transmission of a transactivating signal from the N-terminal region of the androgen receptor to the basal transcription machinery of the cell. A coactivator protein interacting with the activation function 1 (AF-1) transactivation domain of the androgen receptor may have been deficient in this patient. The signal disruption could not be corrected by supplementation with any coactivators known at the time, nor was the absent coactivator protein characterized, which left some in the field unconvinced that a mutant coactivator would explain the mechanism of androgen resistance in CAIS or PAIS patients with a typical AR gene.

XY karyotype
Depending on the mutation, a person with a 46,XY karyotype and AIS can have either a male (MAIS) or female (CAIS) phenotype, or may have genitalia that are only partially masculinized (PAIS). The gonads are testes regardless of phenotype due to the influence of the Y chromosome. A 46,XY female, thus, does not have ovaries, and can not contribute an egg towards conception. In some cases, 46, XY females do form a vestigial uterus and have been able to gestate children. Such examples are rare and have required the use of an egg donor, hormone therapy, and IVF.

Several case studies of fertile 46,XY males with AIS have been published, although this group is thought to be a minority. In some cases, infertile males with MAIS have been able to conceive children after increasing their sperm count through the use of supplementary testosterone.

A genetic male conceived by a man with AIS would not receive his father's X chromosome, thus would neither inherit nor carry the gene for the syndrome. A genetic female conceived in such a way would receive her father's X chromosome, thus would become a carrier.

XX karyotype
Genetic females (46,XX karyotype) have two X chromosomes, thus have two AR genes. A mutation in one (but not both) results in a minimally affected, fertile, female carrier. Some carriers have been noted to have slightly reduced body hair, delayed puberty, and/or tall stature, presumably 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, too, will be a carrier. An affected 46,XY child will have AIS.

A genetic female with mutations in both AR genes could theoretically result from the union of a fertile man with AIS and a female carrier of the gene, or from de novo mutation. However, given the scarcity of fertile AIS men and low incidence of AR mutation, the chances of this occurrence are small. The phenotype of such an individual is a matter of speculation; as of 2010, no such documented case has been published.

Correlation of genotype and phenotype
Individuals with partial AIS, unlike those with the complete or mild forms, present at birth with ambiguous genitalia, and the decision to raise the child as male or female is often not obvious. Unfortunately, little information regarding phenotype can be gleaned from precise knowledge of the AR mutation itself;  the same AR mutation may cause significant variation in the degree of masculinization in different individuals, even among members of the same family. Exactly what causes this variation is not entirely understood, although factors contributing to it could include the lengths of the polyglutamine and polyglycine tracts, sensitivity to and variations in the intrauterine endocrine milieu, the effect of coregulatory proteins active in Sertoli cells, somatic mosaicism, expression of the 5RD2 gene in genital skin fibroblasts, reduced AR transcription and translation from factors other than mutations in the AR coding region, an unidentified coactivator protein, enzyme deficiencies such as 21-hydroxylase deficiency, or other genetic variations such as a mutant steroidogenic factor-1 protein. The degree of variation, however, does not appear to be constant across all AR mutations, and is much more extreme in some. Missense mutations that result in a single amino acid substitution are known to produce the most phenotypic diversity.

Androgens and the androgen receptor
The effects that androgens have on the human body (virilization, masculinization, anabolism, etc.) are not brought about by androgens themselves, but rather are the result of androgens bound to androgen receptors; the androgen receptor mediates the effects of androgens in the human body. Likewise, the androgen receptor itself is generally inactive in the cell until androgen binding occurs.

The following series of steps illustrates how androgens and the androgen receptor work together to produce androgenic effects:

1. Androgen enters the cell. 1. Only certain organs in the body, such as the gonads and the adrenal glands, produce the androgen testosterone.

2. Testosterone is converted into dihydrotestosterone, a chemically similar androgen, in cells containing the enzyme 5-alpha reductase.

3. Both androgens exert their influence through binding with the androgen receptor.

2. Androgen binds with the androgen receptor. 1. The androgen receptor is expressed ubiquitously throughout the tissues of the human body.

2. Before it binds with an androgen, the androgen receptor is bound to heat shock proteins.

3. These heat shock proteins are released upon androgen binding.

4. Androgen binding induces a stabilizing, conformational change in the androgen receptor.

5. The two zinc fingers of the DNA-binding domain are exposed as a result of this new conformation.

6. AR stability is thought to be aided by type II coregulators, which modulate protein folding and androgen binding, or facilitate NH2/carboxyl-terminal interaction.

3. The hormone-activated androgen receptor is phosphorylated. 1. Receptor phosphorylation can occur before androgen binding, although the presence of androgen promotes hyperphosphorylation.

2. The biological ramifications of receptor phosphorylation are unknown.

4. The hormone-activated androgen receptor translocates to the nucleus. 1. Nucleocytoplasmic transport is in part facilitated by an amino acid sequence on the AR called the nuclear localization signal.

2. The AR's nuclear localization signal is primarily encoded in the hinge region of the AR gene.

5. Homodimerization occurs. 1. Dimerization is mediated by the second (nearest the 3' end) zinc finger.

6. DNA binding to regulatory androgen response elements occurs. 1. Target genes contain (or are flanked by) transcriptional enhancer nucleotide sequences that interact with the first zinc finger.

2. These areas are called androgen response elements.

7. Coactivators are recruited by the AR. 1. Type I coactivators (i.e., coregulators) are thought to influence AR transcriptional activity by facilitating DNA occupancy, chromatin remodeling, or the recruitment of general transcription factors associated with RNA polymerase II holocomplex.

8. Target gene transcription ensues.

In this way, androgens bound to androgen receptors regulate the expression of target genes, thus produce androgenic effects.

Theoretically, certain mutant androgen receptors can function without androgens; in vitro studies have demonstrated that a mutant androgen receptor protein can induce transcription in the absence of androgen if its steroid binding domain is deleted. Conversely, the steroid-binding domain may act to repress the AR transactivation domain, perhaps due to the AR's unliganded conformation.

Androgens in fetal development
Human embryos develop similarly for the first six weeks, regardless of genetic sex (46,XX or 46,XY karyotype); the only way to tell the difference between 46,XX or 46,XY embryos during this time period is to look for Barr bodies or a Y chromosome. The gonads begin as bulges of tissue called 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 called indifferent gonads. By the sixth week, the indifferent gonads begin to differentiate according to genetic sex. If the karyotype is 46,XY, testes develop due to the influence of the Y chromosome's SRY gene. This process does not require the presence of androgen, nor a functional androgen receptor.

Until around the seventh week of development, the embryo has indifferent sex accessory ducts, which consist of two pairs of ducts: the Müllerian ducts and the Wolffian ducts. Sertoli cells within the testes secrete anti-Müllerian hormone around this time to suppress the development of the Müllerian ducts, and cause 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 will not continue to develop by default. In the presence of testosterone and functional androgen receptors, the Wolffian ducts develop into the epididymides, vasa deferentia, and seminal vesicles. If the testes fail to secrete testosterone, or the androgen receptors do not function properly, the Wolffian ducts degenerate.

Masculinization of the male external genitalia (the penis, penile urethra, and scrotum), as well as the prostate, are dependent on the androgen dihydrotestosterone. Testosterone is converted into dihydrotestosterone by the 5-alpha reductase enzyme. If this enzyme is absent or deficient, then dihydrotestosterone is not created, and the external male genitalia do not develop properly. As is the case with the internal male genitalia, a functional androgen receptor is needed for dihydrotestosterone to regulate the transcription of target genes involved in development.

Pathogenesis of AIS
Mutations in the androgen receptor gene can cause problems with any of the steps involved in androgenization, from the synthesis of the androgen receptor protein itself, through the transcriptional ability of the dimerized, androgen-AR complex. AIS can result if even one of these steps is significantly disrupted, as each step is required for androgens to activate the AR successfully and regulate gene expression. Exactly which steps a particular mutation will impair can be predicted, to some extent, by identifying the area of the AR in which the mutation resides. This predictive ability is primarily retrospective in origin; the different functional domains of the AR gene have been elucidated by analyzing the effects of specific mutations in different regions of the AR. For example, mutations in the steroid binding domain have been known to affect androgen binding affinity or retention, mutations in the hinge region have been known to affect nuclear translocation, mutations in the DNA-binding domain have been known to affect dimerization and binding to target DNA, and mutations in the transactivation domain have been known to affect target gene transcription regulation. Unfortunately, even when the affected functional domain is known, predicting the phenotypical consequences of a particular mutation (see Correlation of genotype and phenotype) is difficult.

Some mutations can adversely impact more than one functional domain. For example, a mutation in one functional domain can have deleterious effects on another by altering the way in which the domains interact. A single mutation can affect all downstream functional domains if a premature stop codon or framing error results; such a mutation can result in a completely unusable (or unsynthesizable) androgen receptor protein. The steroid binding domain is particularly vulnerable to the effects of a premature stop codon or framing error, since it occurs at the end of the gene, and its information is thus more likely to be truncated or misinterpreted than other functional domains.

Other, more complex relationships have been observed as a consequence of mutated AR; some mutations associated with male phenotypes have been linked to male breast cancer, prostate cancer, or in the case of spinal and bulbar muscular atrophy, disease of the central nervous system. The form of breast cancer seen in some men with PAIS is caused by a mutation in the AR's DNA-binding domain. This mutation is thought to cause a disturbance of the AR's target gene interaction that allows it to act at certain additional targets, possibly in conjunction with the estrogen receptor protein, to cause cancerous growth. The pathogenesis of spinal and bulbar muscular atrophy (SBMA) demonstrates that even the mutant AR protein itself can result in pathology. The trinucleotide repeat expansion of the polyglutamine tract of the AR gene that is associated with SBMA results in the synthesis of a misfolded AR protein that the cell fails to proteolyze and disperse properly. These misfolded AR proteins form aggregates in the cell cytoplasm and nucleus. Over the course of 30 to 50 years, these aggregates accumulate and have a cytotoxic effect, eventually resulting in the neurodegenerative symptoms associated with SBMA.

Diagnosis
The phenotypes that result from the insensitivity to androgens are not unique to AIS, thus the diagnosis of AIS requires thorough exclusion of other causes. Clinical findings indicative of AIS include the presence of a short vagina or undermasculinized genitalia,  partial or complete regression of Müllerian structures, bilateral nondysplastic testes, and impaired spermatogenesis and/or virilization. Laboratory findings include a 46,XY karyotype and typical or elevated postpubertal testosterone, luteinizing hormone, and estradiol levels. The androgen binding activity of genital skin fibroblasts is typically diminished, although exceptions have been reported. Conversion of testosterone to dihydrotestosterone may be impaired. The diagnosis of AIS is confirmed if androgen receptor gene sequencing reveals a mutation, although not all individuals with AIS (particularly PAIS) will have an AR mutation (see Other Causes).

Each of the three types of AIS (complete, partial, and mild) has a different list of differential diagnoses to consider. However, cases have been reported of individuals with both AIS and certain diagnoses listed here, such as Klinefelter syndrome or Turner syndrome with mosaicism. Depending on the form of AIS suspected, the list of differentials can include: • 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

Classification

AIS is broken down into three classes based on phenotype: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), and mild androgen insensitivity syndrome (MAIS). A supplemental system of phenotypic grading that uses seven classes instead of the traditional three was proposed by pediatric endocrinologist Charmian A. Quigley et al. in 1995. The first six grades of the scale, grades 1 through 6, are differentiated by the degree of genital masculinization; grade 1 is indicated when the external genitalia is fully masculinized, grade 6 is indicated when the external genitalia is fully feminized, and grades 2 through 5 quantify four degrees of decreasingly masculinized genitalia that lie in the interim. Grade 7 is indistinguishable from grade 6 until puberty, and is thereafter differentiated by the presence of secondary terminal hair; grade 6 is indicated when secondary terminal hair is present, whereas grade 7 is indicated when it is absent. The Quigley scale can be used in conjunction with the traditional three classes of AIS to provide additional information regarding the degree of genital masculinization, and is particularly useful when the diagnosis is PAIS.

Management
Management of AIS is currently limited to symptomatic management; no method is currently available to correct the malfunctioning androgen receptor proteins produced by AR gene mutations. Areas of management include sex assignment, genitoplasty, gonadectomy in relation to tumor risk, hormone replacement therapy, genetic counseling, and psychological counseling.

Epidemiology
AIS represents about 15% to 20% of DSDs and affects 1 in 20,000 to 1 in 64,000 males.

Estimates for the incidence of androgen insensitivity syndrome are based on a relatively small population size, thus are known to be imprecise. CAIS is estimated to occur in one of every 20,400 46,XY births. A nationwide survey in the Netherlands based on patients with genetic confirmation of the diagnosis estimates that the minimal incidence of CAIS is one in 99,000. The incidence of PAIS is estimated to be one in 130,000. Due to its subtle presentation, MAIS is not typically investigated except in the case of male infertility, thus its true prevalence is unknown.

Preimplantation genetic diagnosis
Preimplantation genetic diagnosis (PGD or PIGD) refers to genetic profiling of embryos prior to implantation (as a form of embryo profiling), and sometimes even of oocytes prior to fertilization. When used to screen for a specific genetic sequence, its main advantage is that it avoids selective pregnancy termination, as the method makes it highly likely that a selected embryo will be free of the condition under consideration.

In the UK, AIS appears on a list of serious genetic diseases that may be screened for via PGD. Some ethicists, clinicians, and intersex advocates have argued that screening embryos to specifically exclude intersex traits is based on social and cultural norms as opposed to medical necessity.

History
Recorded descriptions of the effects of AIS date back hundreds of years, although significant understanding of its underlying histopathology did not occur until the 1950s. The taxonomy and nomenclature associated with androgen insensitivity went through a significant evolution that paralleled this understanding.

Timeline of major milestones

 * 1950: Lawson Wilkins administers daily methyltestosterone to a karyotype 46,XY female patient, who shows no signs of virilization. His experiment is the first documented demonstration of the pathophysiology of AIS.
 * 1970: Mary F. Lyon and Susan Hawkes reported that a gene on the X chromosome caused complete insensitivity to androgens in mice.
 * 1981: Barbara Migeon et al. narrowed down the locus of the human androgen receptor gene (or a factor controlling the androgen receptor gene) to somewhere between Xq11 and Xq13.
 * 1988: The human androgen receptor gene is first cloned and partially analyzed by multiple parties.  Terry Brown et al. reported the first mutations proven to cause AIS.
 * 1989: Terry Brown et al. reported the exact locus of the AR gene (Xq11-Xq12), and Dennis Lubahn et al. published its intron-exon boundaries.
 * 1994: The androgen receptor gene mutations database was created to provide a comprehensive listing of mutations published in medical journals and conference proceedings.

Early terminology
The first descriptions of the effects of AIS appeared in the medical literature as individual case reports or as part of a comprehensive description of intersex physicalities. In 1839, Scottish obstetrician Sir James Young Simpson published one such description in an exhaustive study of intersexuality that has been credited with advancing the medical community's understanding of the subject. Simpson's system of taxonomy, however, was far from the first; taxonomies or descriptions for the classification of intersexuality were developed by Italian physician and physicist Fortuné Affaitati in 1549, French surgeon Ambroise Paré in 1573,  French physician and sexology pioneer Nicolas Venette in 1687 (under the pseudonym Vénitien Salocini),  and French zoologist Isidore Geoffroy Saint-Hilaire in 1832. All five of these authors used the colloquial term "hermaphrodite" as the foundation of their taxonomies, although Simpson himself questioned the propriety of the word in his publication. Use of the word "hermaphrodite" in the medical literature has persisted to this day, although its propriety is still in question. An alternative system of nomenclature has been recently suggested, but the subject of exactly which word or words should be used in its place still one of much debate.

Pseudohermaphroditism
"Pseudohermaphroditism" has, until very recently, been the term used in the medical literature to describe the condition of an individual whose gonads do not match the expected external genitalia in of their sex. For example, 46,XY individuals who have a female phenotype, but also have testes instead of ovaries—a group that includes all individuals with CAIS, as well as some individuals with PAIS—are classified as having "male pseudohermaphroditism", while individuals with both an ovary and a testis (or at least one ovotestis) are classified as having "true hermaphroditism". Use of the word in the medical literature antedates the discovery of the chromosome, thus its definition has not always taken karyotype into account when determining an individual's sex. Previous definitions of "pseudohermaphroditism" relied on perceived inconsistencies between the internal and external organs; the "true" sex of an individual was determined by the internal organs, and the external organs determined the "perceived" sex of an individual.

German-Swiss pathologist Edwin Klebs is sometimes noted for using the word "pseudohermaphroditism" in his taxonomy of intersexuality in 1876, although the word is clearly not his invention as is sometimes reported; the history of the word "pseudohermaphrodite" and the corresponding desire to separate "true" hermaphrodites from "false", "spurious", or "pseudo" hermaphrodites, dates back to at least 1709, when Dutch anatomist Frederik Ruysch used it in a publication describing a subject with testes and a mostly female phenotype. "Pseudohermaphrodite" also appeared in the Acta Eruditorum later that same year, in a review of Ruysch's work. Also some evidence indicates the word was already being used by the German and French medical community long before Klebs used it; German physiologist Johannes Peter Müller equated "pseudohermaphroditism" with a subclass of hermaphroditism from Saint-Hilaire's taxonomy in a publication dated 1834, and by the 1840s "pseudohermaphroditism" was appearing in several French and German publications, including dictionaries.

Testicular feminization
In 1953, American gynecologist John Morris provided the first full description of what he called "testicular feminization syndrome" based on 82 cases compiled from the medical literature, including two of his own patients. The term "testicular feminization" was coined to reflect Morris' observation that the testicles in these patients produced a hormone that had a feminizing effect on the body, a phenomenon now understood to be due to the inaction of androgens, and subsequent aromatization of testosterone into estrogen. A few years before Morris published his landmark paper, Lawson Wilkins had shown through experiment that unresponsiveness of the target cell to the action of androgenic hormones was a cause of "male pseudohermaphroditism". Wilkins' work, which clearly demonstrated the lack of a therapeutic effect when 46,XY patients were treated with androgens, caused a gradual shift in nomenclature from "testicular feminization" to "androgen resistance".

Other names
A distinct name has been given to many of the various presentations of AIS, such as Reifenstein syndrome (1947), Goldberg-Maxwell syndrome (1948), Morris' syndrome (1953), Gilbert-Dreyfus syndrome (1957), Lub's syndrome (1959), "incomplete testicular feminization" (1963), Rosewater syndrome (1965), and Aiman's syndrome (1979). Since it was not understood that these different presentations were all caused by the same set of mutations in the androgen receptor gene, a unique name was given to each new combination of symptoms, resulting in a complicated stratification of seemingly disparate disorders.

Over the last 60 years, as reports of strikingly different phenotypes were reported to occur even among members of the same family, and as steady progress was made towards the understanding of the underlying molecular pathogenesis of AIS, these disorders were found to be different phenotypic expressions of one syndrome caused by molecular defects in the androgen receptor gene.

AIS is now the accepted terminology for the syndromes resulting from unresponsiveness of the target cell to the action of androgenic hormones. CAIS encompasses the phenotypes previously described by "testicular feminization", Morris' syndrome, and Goldberg-Maxwell syndrome; PAIS includes Reifenstein syndrome, Gilbert-Dreyfus syndrome, Lub's syndrome, "incomplete testicular feminization", and Rosewater syndrome;   and MAIS includes Aiman's syndrome.

The more virilized phenotypes of AIS have sometimes been described as "undervirilized male syndrome", "infertile male syndrome", "undervirilized fertile male syndrome", etc., before evidence was reported that these conditions were caused by mutations in the AR gene. These diagnoses were used to describe a variety of mild defects in virilization; as a result, the phenotypes of some men who have been diagnosed as such are better described by PAIS (e.g. micropenis, hypospadias, and undescended testes), while others are better described by MAIS (e.g. isolated male infertility or gynecomastia).

Society and culture
In the film Orchids, My Intersex Adventure, Phoebe Hart and her sister Bonnie Hart, both women with CAIS, documented their exploration of AIS and other intersex issues.

Recording artist Dalea is a Hispanic-American Activist who is public about her CAIS. She has given interviews about her condition and founded Girl Comet, a non-profit diversity awareness and inspiration initiative.

In 2017, fashion model Hanne Gaby Odiele disclosed that they were born with androgen insensitivity syndrome. As a child, they underwent medical procedures relating to the condition, which they said took place without their or their parents' informed consent. They were told about their intersex condition weeks before beginning their modelling career.

In the 1991 Japanese horror novel Ring and its sequels, by Koji Suzuki (later adapted into Japanese, Korean, and American films), the central antagonist Sadako has this syndrome, as revealed by Dr Nagao when confronted by Ryuji and Asakawa. Sadako's condition is referred to by the earlier name "testicular feminisation syndrome".

In season 2, episode 13 ("Skin Deep") of the TV series House, the main patient's cancerous testicle is mistaken for an ovary due to the patient's undiscovered CAIS. The episode has been criticized for its medical inaccuracy as well as its stigmatizing and offensive portrayal of CAIS.

In season 2 of the MTV series Faking It, a character has CAIS. The character, Lauren Cooper, played by Bailey De Young, was the first intersex series regular on American television.

In season 8, episode 11 ("Delko for the Defense") of the TV series CSI: Miami, the primary suspect has AIS which gets him off a rape charge.

In series 8, episode 5 of Call the Midwife, a woman discovers that she has AIS. She attends a cervical smear and brings up that she has never had a period, and is concerned about having children as she is about to be married. She is then diagnosed with "testicular feminisation syndrome", the old term for AIS.

People with AIS

 * Kitty Anderson (activist)
 * Eden Atwood
 * Bonnie Hart
 * Phoebe Hart
 * Maria José Martínez-Patiño
 * Hanne Gaby Odiele
 * Santhi Soundarajan
 * Miriam van der Have
 * Kimberly Zieselman

People with Complete androgen insensitivity syndrome

 * Georgiann Davis
 * Seven Graham
 * Alicia Roth Weigel

People with Partial androgen insensitivity syndrome

 * Tony Briffa
 * Favorinus of Arelate has been described as having partial androgen insensitivity syndrome.
 * Small Luk
 * Eliana Rubashkyn
 * Sean Saifa Wall
 * Sogto Ochirov

title: Androgen insensitivity syndrome


text:
Alexander Pushkin

Alexander Sergeyevich Pushkin (Александр Сергеевич Пушкин, ; 6 June 1799 – 10 February 1837) was a Russian poet, playwright, and novelist of the Romantic era. He is considered by many to be the greatest Russian poet,  as well as the founder of modern Russian literature.

Pushkin was born into the Russian nobility in Moscow. His father, Sergey Lvovich Pushkin, belonged to an old noble family. One of his maternal great-grandfathers was Major-General Abram Petrovich Gannibal, a nobleman of African origin who was kidnapped from his homeland by the Ottomans, then freed by the Russian Emperor and raised in the Emperor's court household as his godson.

He published his first poem at the age of 15, and was widely recognized by the literary establishment by the time of his graduation from the Tsarskoye Selo Lyceum. Upon graduation from the Lycée, Pushkin recited his controversial poem "Ode to Liberty", one of several that led to his exile by Emperor Alexander I. While under strict surveillance by the Emperor's political police and unable to publish, Pushkin wrote his most famous play, Boris Godunov. His novel in verse Eugene Onegin was serialized between 1825 and 1832. Pushkin was fatally wounded in a duel with his wife's alleged lover and her sister's husband, Georges-Charles de Heeckeren d'Anthès, also known as Dantes-Gekkern, a French officer serving with the Chevalier Guard Regiment.

Ancestry
Pushkin's father, Sergei Lvovich Pushkin (1767–1848), was descended from a distinguished family of the Russian nobility that traced its ancestry back to the 12th century. Pushkin's mother, Nadezhda (Nadya) Ossipovna Gannibal (1775–1836), was descended through her paternal grandmother from German and Scandinavian nobility. She was the daughter of Ossip Abramovich Gannibal (1744–1807) and his wife, Maria Alekseyevna Pushkina (1745–1818).

Ossip Abramovich Gannibal's father, Pushkin's great-grandfather, was Abram Petrovich Gannibal (1696–1781), a Eritrean page kidnapped and taken to Constantinople as a gift for the Ottoman Sultan and later transferred to Russia as a gift for Peter the Great. Abram wrote in a letter to Empress Elizabeth, Peter the Great's daughter, that Gannibal was from the town of "Lagon". Largely on the basis of a mythical biography by Gannibal's son-in-law Rotkirkh, some historians concluded from this that Gannibal was born in a village called Geza-Lamza near Dubarwa in the Seraye province of Mdre Bahri kingdom in today's Eritrea.

Vladimir Nabokov, when researching Eugene Onegin, cast serious doubt on this origin theory. Later research by the scholars Dieudonné Gnammankou and Hugh Barnes eventually conclusively established that Gannibal was instead born in Central Africa, in an area bordering Lake Chad in modern-day Cameroon. After education in France as a military engineer, Gannibal became governor of Reval and eventually Général en Chief (the third most senior army rank) in charge of the building of sea forts and canals in Russia.

Early life
Born in Moscow, Pushkin was entrusted to nursemaids and French tutors, and spoke mostly French until the age of ten. He became acquainted with the Russian language through communication with household serfs and his nanny, Arina Rodionovna, whom he loved dearly and to whom he was more attached than to his own mother.

He published his first poem at the age of 15. When he finished school, as part of the first graduating class of the prestigious Imperial Lyceum in Tsarskoye Selo, near Saint Petersburg, his talent was already widely recognized on the Russian literary scene. At the Lyceum, he was a student of David Mara, known in Russia as David de Boudry, a younger brother of French revolutionary Jean-Paul Marat. After school, Pushkin plunged into the vibrant and raucous intellectual youth culture of St. Petersburg, which was then the capital of the Russian Empire. In 1820, he published his first long poem, Ruslan and Ludmila, with much controversy about its subject and style.

Social activism
While at the Lyceum, Pushkin was heavily influenced by the Kantian liberal individualist teachings of Alexander Kunitsyn, whom Pushkin would later commemorate in his poem 19 October. Pushkin also immersed himself in the thought of the French Enlightenment, to which he would remain permanently indebted throughout his life, especially Voltaire, whom he described as "the first to follow the new road, and to bring the lamp of philosophy into the dark archives of history".

Pushkin gradually became committed to social reform, and emerged as a spokesman for literary radicals. That angered the government and led to his transfer from the capital in May 1820. He went to the Caucasus and to Crimea and then to Kamianka and Chișinău in Bessarabia, where he became a Freemason.

He joined the Filiki Eteria, a secret organization whose purpose was to overthrow Ottoman rule in Greece and establish an independent Greek state. He was inspired by the Greek Revolution and when the war against the Ottoman Empire broke out, he kept a diary recording the events of the national uprising.

Rise
He stayed in Chișinău until 1823 and wrote two Romantic poems which brought him acclaim: The Captive of the Caucasus and The Fountain of Bakhchisaray. In 1823, Pushkin moved to Odessa, where he again clashed with the government, which sent him into exile on his mother's rural estate of Mikhailovskoye, near Pskov, from 1824 to 1826.

In Mikhaylovskoye, Pushkin wrote nostalgic love poems which he dedicated to Elizaveta Vorontsova, wife of Malorossia's General-Governor. Then Pushkin worked on his verse-novel Eugene Onegin.

In Mikhaylovskoye, in 1825, Pushkin wrote the poem To***. It is generally believed that he dedicated this poem to Anna Kern, but there are other opinions. Poet Mikhail Dudin believed that the poem was dedicated to the serf Olga Kalashnikova. Pushkinist Kira Victorova believed that the poem was dedicated to the Empress Elizaveta Alekseyevna. Vadim Nikolayev argued that the idea about the Empress was marginal and refused to discuss it, while trying to prove that poem had been dedicated to Tatyana Larina, the heroine of Eugene Onegin.

Authorities summoned Pushkin to Moscow after his poem Ode to Liberty was found among the belongings of the rebels from the Decembrist Uprising (1825). After his exile in 1820 Pushkin's friends and family continually petitioned for his release, sending letters and meeting Emperor Alexander I and then Emperor Nicholas I on the heels of the Decembrist Uprising. Upon meeting Emperor Nicholas I Pushkin obtained his release from exile and began to work as the emperor's Titular Counsel of the National Archives. However, because insurgents in the Decembrist Uprising (1825) in Saint Petersburg had kept some of Pushkin's earlier political poems, the emperor retained strict control of everything Pushkin published and he was banned from travelling at will.

During that same year (1825) Pushkin also wrote what would become his most famous play, the drama Boris Godunov, while at his mother's estate. He could not, however, gain permission to publish it until five years later. The original and uncensored version of the drama was not staged until 2007.

Around 1825–1829 he met and befriended the Polish poet Adam Mickiewicz, during exile in central Russia. In 1829 he travelled through the Caucasus to Erzurum to visit friends fighting in the Russian army during the Russo-Turkish War. At the end of 1829 Pushkin wanted to set off on a journey abroad, the desire reflected in his poem Let's go, I'm ready. He applied for permission for the journey but received negative response from Nicholas I on 17 January 1830.

Around 1828 Pushkin met Natalia Goncharova, then 16 years old and one of the most talked-about beauties of Moscow. After much hesitation Natalia accepted a proposal of marriage from Pushkin in April 1830, but not before she received assurances that the Tsarist government had no intention of persecuting the libertarian poet. Later Pushkin and his wife became regulars of court society. They officially became engaged on 6 May 1830 and sent out wedding invitations. Owing to an outbreak of cholera and other circumstances, the wedding was delayed for a year. The ceremony took place on 18 February 1831 (Old Style) in the Great Ascension Church on Bolshaya Nikitskaya Street in Moscow.

When the Emperor gave Pushkin the lowest court title, Gentleman of the Chamber, the poet became enraged, feeling that the Emperor intended to humiliate him by implying that he was being admitted to court not on his own merits but solely so that his wife, who had many admirers including the Emperor himself, could properly attend court balls. Pushkin's marriage to Goncharova was largely a happy one, but his wife’s characteristic flirtatiousness and frivolity would lead to his fatal duel seven years later, for Pushkin had a highly jealous temperament.

In 1831, during the period of Pushkin's growing literary influence, he met one of Russia's other great early writers, Nikolai Gogol. After reading Gogol's 1831–1832 volume of short stories Evenings on a Farm Near Dikanka, Pushkin supported him and would feature some of Gogol's most famous short stories in the magazine The Contemporary, which he founded in 1836.

Death
By the autumn of 1836, Pushkin was falling into greater and greater debt and faced scandalous rumours that his wife was having a love affair. On 4 November, he sent a challenge to a duel to Georges d'Anthès, also known as Dantes-Gekkern. Jacob van Heeckeren, d'Anthès' adoptive father, asked that the duel be delayed by two weeks. With efforts by the poet's friends, the duel was cancelled.

On 17 November, d'Anthès proposed to Natalia Goncharova's sister, Ekaterina. The marriage did not resolve the conflict. D'Anthès continued to pursue Natalia Goncharova in public and rumours that d'Anthès had married Natalia's sister just to save her reputation circulated.

On 26 January (7 February in the Gregorian calendar) 1837 Pushkin sent a "highly insulting letter" to Gekkern. The only answer to that letter could be a challenge to a duel, as Pushkin knew. Pushkin received the formal challenge to a duel through his sister-in-law, Ekaterina Gekkerna, approved by d'Anthès, on the same day through the attaché of the French Embassy, Viscount d'Archiac.

Pushkin asked Arthur Magenis, then attaché to the British Consulate-General in Saint Petersburg, to be his second. Magenis did not formally accept but on 26 January (7 February) approached Viscount d'Archiac to attempt a reconciliation; however d'Archiac refused to speak with him as he was not yet officially Pushkin's second. Magenis, unable to find Pushkin in the evening, sent him a letter through a messenger at 2 o'clock in the morning declining to be his second, as the possibility of a peaceful settlement had already been quashed, and the traditional first task of the second was to try to bring about a reconciliation.

The pistol duel with d'Anthès took place on 27 January (8 February) at the Black River, without the presence of a second for Pushkin. The duel they fought was of a kind known as a "barrier duel". The rules of this type dictated that the duellists began at an agreed distance. After the signal to begin, they walked towards each other, closing the distance. They could fire at any time they wished, but the duellist that shot first was required to stand still and wait for the other to shoot back at his leisure.

D'Anthès fired first, critically wounding Pushkin; the bullet entered at his hip and penetrated his abdomen. D'Anthès was only lightly wounded in the right arm by Pushkin's shot. Two days later, at 2.45 pm on 29 January (10 February), Pushkin died of peritonitis.

At Pushkin's wife's request he was put in the coffin in evening dress, not in chamber-cadet uniform, the uniform provided by the emperor. The funeral service was initially assigned to St Isaac's Cathedral but was moved to Konyushennaya church. Many people attended. After the funeral the coffin was lowered into the basement, where it stayed until 3 February, when it was removed to Pskov province. Pushkin was buried in the grounds of Svyatogorsky monastery in present-day Pushkinskiye Gory, near Pskov, beside his mother. His last home is now a museum.

Descendants
Pushkin had four children from his marriage to Natalia: Maria (b. 1832), Alexander (b. 1833), Grigory (b. 1835) and Natalia (b. 1836), the last of whom married morganatically Prince Nikolaus Wilhelm of Nassau of the House of Nassau-Weilburg and was granted the title of Countess of Merenberg. Her daughter Sophie married Grand Duke Michael Mikhailovich of Russia, a grandson of Emperor Nicholas I.

Only the lines of Alexander and Natalia still remain. Natalia's granddaughter, Nadejda, married into the extended British royal family, her husband being the uncle of Prince Philip, Duke of Edinburgh, and is the grandmother of the present Marquess of Milford Haven. Descendants of the poet now live around the globe in the United Kingdom, the Czech Republic, Germany, Belgium, Luxembourg and the United States.

Legacy

On 6 June 2009, Google celebrated Alexander Pushkin's Birthday with a doodle.

Literary
Critics consider many of his works masterpieces, such as the poem The Bronze Horseman and the drama The Stone Guest, a tale of the fall of Don Juan. His poetic short drama Mozart and Salieri (like The Stone Guest, one of the so-called four Little Tragedies, a collective characterization by Pushkin himself in 1830 letter to Pyotr Pletnyov ) was the inspiration for Peter Shaffer's Amadeus as well as providing the libretto (almost verbatim) to Rimsky-Korsakov's opera Mozart and Salieri.

Pushkin is also known for his short stories. In particular his cycle The Tales of the Late Ivan Petrovich Belkin, including The Shot, were well received. According to the literary theorist Kornelije Kvas, "'the narrative logic and the plausibility of that which is narrated, together with the precision, conciseness – economy of the presentation of reality – all of the above is achieved in Tales of Belkin, especially, and most of all in the story The Stationmaster. Pushkin is the progenitor of the long and fruitful development of Russian realist literature, for he manages to attain the realist ideal of a concise presentation of reality'." Pushkin himself preferred his verse novel Eugene Onegin, which he wrote over the course of his life and which, starting a tradition of great Russian novels, follows a few central characters but varies widely in tone and focus.

Onegin is a work of such complexity that, though it is only about a hundred pages long, translator Vladimir Nabokov needed two full volumes of material to fully render its meaning into English. Because of this difficulty in translation, Pushkin's verse remains largely unknown to English readers. Even so Pushkin has profoundly influenced western writers such as Henry James. Pushkin wrote The Queen of Spades, a short story frequently anthologized in English translation.

Musical
Pushkin's works also provided fertile ground for Russian composers. Glinka's Ruslan and Lyudmila is the earliest important Pushkin-inspired opera, and a landmark in the tradition of Russian music. Tchaikovsky's operas Eugene Onegin (1879) and The Queen of Spades (Pikovaya Dama, 1890) became perhaps better known outside of Russia than Pushkin's own works of the same name.

Mussorgsky's monumental Boris Godunov (two versions, 1868–9 and 1871–2) ranks as one of the very finest and most original of Russian operas. Other Russian operas based on Pushkin include Dargomyzhsky's Rusalka and The Stone Guest; Rimsky-Korsakov's Mozart and Salieri, Tale of Tsar Saltan, and The Golden Cockerel; Cui's Prisoner of the Caucasus, Feast in Time of Plague, and The Captain's Daughter; Tchaikovsky's Mazeppa; Rachmaninoff's one-act operas Aleko (based on The Gypsies) and The Miserly Knight; Stravinsky's Mavra, and Nápravník's Dubrovsky.

Additionally, ballets and cantatas, as well as innumerable songs, have been set to Pushkin's verse (including even his French-language poems, in Isabelle Aboulker's song cycle "Caprice étrange"). Suppé, Leoncavallo and Malipiero have also based operas on his works. Composers Yudif Grigorevna Rozhavskaya, Galina Konstantinovna Smirnova, Yevgania Yosifovna Yakhina, Maria Semyonovna Zavalishina, Zinaida Petrovna Ziberova composed folk songs using Pushkin's text.

The Desire of Glory, which has been dedicated to Elizaveta Vorontsova, was set to music by David Tukhmanov, as well as Keep Me, Mine Talisman – by Alexander Barykin and later by Tukhmanov.

Romanticism
Pushkin is considered by many to be the central representative of Romanticism in Russian literature although he was not unequivocally known as a Romantic. Russian critics have traditionally argued that his works represent a path from Neoclassicism through Romanticism to Realism. An alternative assessment suggests that "he had an ability to entertain contrarities which may seem Romantic in origin, but are ultimately subversive of all fixed points of view, all single outlooks, including the Romantic" and that "he is simultaneously Romantic and not Romantic".

Russian literature
Pushkin is usually credited with developing Russian literature. He is seen as having originated the highly nuanced level of language which characterizes Russian literature after him, and he is also credited with substantially augmenting the Russian lexicon. Whenever he found gaps in the Russian vocabulary, he devised calques. His rich vocabulary and highly-sensitive style are the foundation for modern Russian literature. His accomplishments set new records for development of the Russian language and culture. He became the father of Russian literature in the 19th century, marking the highest achievements of the 18th century and the beginning of literary process of the 19th century. He introduced Russia to all the European literary genres as well as a great number of West European writers. He brought natural speech and foreign influences to create modern poetic Russian. Though his life was brief, he left examples of nearly every literary genre of his day: lyric poetry, narrative poetry, the novel, the short story, the drama, the critical essay and even the personal letter.

According to Vladimir Nabokov, Pushkin's idiom combined all the contemporaneous elements of Russian with all he had learned from Derzhavin, Zhukovsky, Batyushkov, Karamzin and Krylov:

 * 1) The poetical and metaphysical strain that still lived in Church Slavonic forms and locutions
 * 2) Abundant and natural gallicisms
 * 3) Everyday colloquialisms of his set
 * 4) Stylized popular speech by combining the famous three styles (low, medium elevation, high) dear to the pseudoclassical archaists and adding the ingredients of Russian romanticists with a pinch of parody.

His work as a critic and as a journalist marked the birth of Russian magazine culture which included him devising and contributing heavily to one of the most influential literary magazines of the 19th century, the Sovremennik (The Contemporary, or Современник). Pushkin inspired the folk tales and genre pieces of other authors: Leskov, Yesenin and Gorky. His use of Russian formed the basis of the style of novelists Ivan Turgenev, Ivan Goncharov and Leo Tolstoy, as well as that of subsequent lyric poets such as Mikhail Lermontov. Pushkin was analysed by Nikolai Gogol, his successor and pupil, and the great Russian critic Vissarion Belinsky, who produced the fullest and deepest critical study of Pushkin's work, which still retains much of its relevance.

Soviet centennial celebrations
The centennial year of Pushkin's death, 1937, was one of the most significant Soviet-era literary centennials in Stalinist Russia, rivaled only by the 1928 centennial commemorating Leo Tolstoy's birth. Despite the public display of visage on ever present billboards and candy wrappers, Pushkin's "image" conflicted with that of the ideal Soviet (he was reputed as a libertine with unrepentant aristocratic tendencies) and was subject to a repressive revisionism, similar to the Stalinist state's clean up of Tolstoy's Christian anarchism.

Honours

 * Shortly after Pushkin's death, contemporary Russian romantic poet Mikhail Lermontov wrote "Death of the Poet". The poem, which ended with a passage blaming the aristocracy being (as oppressors of freedom) the true culprits in Pushkin's death, was not published (nor could have been) but was informally circulated in St. Petersburg. Lermontov was arrested and exiled to a regiment in the Caucasus.
 * Montenegrin poet and ruler Petar II Petrović-Njegoš included in his 1846 poetry collection Ogledalo srpsko (The Serbian Mirror) a poetic ode to Pushkin, titled Sjeni Aleksandra Puškina.
 * In 1929, Soviet writer, Leonid Grossman, published a novel, The d'Archiac Papers, telling the story of Pushkin's death from the perspective of a French diplomat, being a participant and a witness of the fatal duel. The book describes him as a liberal and a victim of the Tsarist regime. In Poland the book was published under the title Death of the Poet.
 * In 1937, the town of Tsarskoye Selo was renamed Pushkin in his honour.
 * There are several museums in Russia dedicated to Pushkin, including two in Moscow, one in Saint Petersburg, and a large complex in Mikhaylovskoye.
 * Pushkin's death was portrayed in the 2006 biographical film Pushkin: The Last Duel. The film was directed by Natalya Bondarchuk. Pushkin was portrayed on screen by Sergei Bezrukov.
 * His life was dramatised in the 1951 Australian radio play The Golden Cockerel
 * In 2000, the Statue of Alexander Pushkin (Washington, D.C.) was erected as part of a cultural exchange between the cities of Moscow and Washington. In return, a statue of the American poet Walt Whitman was erected in Moscow.
 * The Pushkin Trust was established in 1987 by the Duchess of Abercorn to commemorate the creative legacy and spirit of her ancestor and to release the creativity and imagination of the children of Ireland by providing them with opportunities to communicate their thoughts, feelings and experiences.
 * A minor planet, 2208 Pushkin, discovered in 1977 by Soviet astronomer Nikolai Chernykh, is named after him. A crater on Mercury is also named in his honour.
 * MS Aleksandr Pushkin, second ship of the Russian Ivan Franko class (also referred to as "poet" or "writer" class).
 * A station of Tashkent metro was named in his honour.
 * The Pushkin Hills and Pushkin Lake were named in his honour in Ben Nevis Township, Cochrane District, in Ontario, Canada.
 * UN Russian Language Day, established by the United Nations in 2010 and celebrated each year on 6 June, was scheduled to coincide with Pushkin's birthday.
 * A statue of Pushkin was unveiled inside the Mehan Garden in Manila, Philippines to commemorate the Philippines–Russia relations in 2010.
 * The Alexander Pushkin diamond, the second largest found in Russia and the former territory of the USSR, was named after him.
 * On 28 November 2009, a Pushkin Monument was erected in Asmara, capital of Eritrea.
 * In 2005 a monument to Pushkin and his grandmother Maria Hannibal was commissioned by an enthusiast of Russian culture Just Rugel in Zakharovo, Russia. Sculptor V. Kozinin
 * In 2019, Moscow's Sheremetyevo International Airport was named after Pushkin in accordance to the Great Names of Russia contest.
 * Following the 2022 Russian invasion of Ukraine monuments dedicated to Pushkin in Ukraine were demolished and Pushkin streets were renamed.
 * In December 2022, a monument to the poet Alexander Sergeevich Pushkin was unveiled on the territory of Gymnasium No. 1 in Sevastopol. The bust of the poet was created by the sculptor Denis Stritovich.

Narrative poems

 * 1820 – Ruslan i Ludmila (Руслан и Людмила); English translation: Ruslan and Ludmila
 * 1820–21 – Kavkazskiy plennik (Кавказский пленник); English translation: The Prisoner of the Caucasus
 * 1821 – Gavriiliada (Гавриилиада); English translation: The Gabrieliad
 * 1821–22 – Bratia razboyniki (Братья разбойники); English translation: The Robber Brothers
 * 1823 – Bakhchisarayskiy fontan (Бахчисарайский фонтан); English translation: The Fountain of Bakhchisaray
 * 1824 – Tsygany (Цыганы); English translation: The Gypsies
 * 1825 – Graf Nulin (Граф Нулин); English translation: Count Nulin
 * 1829 – Poltava (Полтава)
 * 1830 – Domik v Kolomne (Домик в Коломне); English translation: The Little House in Kolomna
 * 1833 – Andzhelo (Анджело); English translation: Angelo
 * 1833 – Medny vsadnik (Медный всадник); English translation: The Bronze Horseman
 * 1825–1832 (1833) – Evgeniy Onegin (Евгений Онегин); English translation: Eugene Onegin

Drama

 * 1825 – Boris Godunov (Борис Годунов); English translation by Alfred Hayes: Boris Godunov
 * 1830 – Malenkie tragedii (Маленькие трагедии); English translation: Little Tragedies (Pushkin)
 * Kamenny gost (Каменный гость); English translation: The Stone Guest
 * Motsart i Salieri (Моцарт и Сальери); English translation: Mozart and Salieri
 * Skupoy rytsar (Скупой рыцарь); English translations: The Miserly Knight, or The Covetous Knight
 * Pir vo vremya chumy (Пир во время чумы); English translation: A Feast in Time of Plague

Fairy tales in verse

 * 1822 – Царь Никита и сорок его дочерей; English translation: Tsar Nikita and His Forty Daughters
 * 1825 – Жених; English translation: The Bridegroom
 * 1830 – Сказка о попе и о работнике его Балде; English translation: The Tale of the Priest and of His Workman Balda
 * 1830 – Сказка о медведихе; English translation: The Tale of the Female Bear, or The Tale of the Bear (was not finished)
 * 1831 – Сказка о царе Салтане; English translation: The Tale of Tsar Saltan
 * 1833 – Сказка о рыбаке и рыбке; English translation: The Tale of the Fisherman and the Fish
 * 1833 – Сказка о мертвой царевне; English translation: The Tale of the Dead Princess
 * 1834 – Сказка о золотом петушке; English translation: The Tale of the Golden Cockerel

Short poems

 * 1817 – "Ode to Liberty"
 * 1829 – "I Loved You"
 * 1831 – "To the Slanderers of Russia"

Novels

 * 1828 – Arap Petra Velikogo (Арап Петра Великого); English translation: The Moor of Peter the Great, unfinished novel
 * 1829 – Roman v pis'makh (Роман в письмах); English translation: A Novel in Letters, unfinished novel
 * 1836 – Kapitanskaya dochka (Капитанская дочка); English translation: The Captain's Daughter, novel
 * 1836 – Roslavlyov (Рославлев); English translation: Roslavlev, unfinished novel
 * 1841 – Dubrovsky (Дубровский); English translation: Dubrovsky, unfinished novel

Short stories

 * 1831 – Povesti pokoynogo Ivana Petrovicha Belkina (Повести покойного Ивана Петровича Белкина); English translation: The Tales of the Late Ivan Petrovich Belkin
 * Vystrel (Выстрел); English translation: The Shot, short story
 * Metel (Метель); English translation: The Blizzard, short story
 * Grobovschik (Гробовщик); English translation: The Undertaker, short story
 * Stantsionny smotritel (Станционный смотритель); English translation: The Stationmaster, short story
 * Baryshnya-krestianka (Барышня-крестьянка); English translation: The Squire's Daughter, short story
 * 1834 – Pikovaya dama (Пиковая дама); English translation: The Queen of Spades, short story
 * 1834 – Kirjali (Кирджали); English translation: Kirdzhali, short story
 * 1837 – Istoria sela Goryuhina (История села Горюхина); English translation: The Story of the Village of Goryukhino, unfinished short story
 * 1837 – Egypetskie nochi (Египетские ночи); English translation: The Egyptian Nights

Non-fiction

 * 1834 – Istoria Pugachyova (История Пугачева); English translation: A History of Pugachev, study of the Pugachev's Rebellion
 * 1836 – Puteshestvie v Arzrum (Путешествие в Арзрум); English translation: A Journey to Arzrum, travel sketches

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Alexander Pushkin


text:
Pushkin Museum

The Pushkin State Museum of Fine Arts (Музей изобразительных искусств имени А. С. Пушкина, abbreviated as ГМИИ) is the largest museum of European art in Moscow. It is located in Volkhonka street, just opposite the Cathedral of Christ the Saviour. The International musical festival Sviatoslav Richter's December nights has been held in the Pushkin Museum since 1981.

Etymology
Despite its name, the museum has no direct association with the Russian poet Alexander Pushkin, other than as a posthumous commemoration. The facility was founded by professor Ivan Tsvetaev (father of the poet Marina Tsvetaeva) in 1912. Tsvetaev persuaded the millionaire and philanthropist Yuriy Nechaev-Maltsov and the architect Roman Klein of the urgent need to give Moscow a fine arts museum. After going through a number of name changes, particularly in the transition to the Soviet era and the return of the Russian capital to Moscow, the museum was finally renamed to honour Pushkin in 1937, the 100th anniversary of his death.

History
During the Bolshevik Revolution, works by French impressionists and modern artists were confiscated and then exhibited in the Hermitage Museum in Saint Petersburg before being privately stored. In 2019, those works reappeared and some of them rejoined the Pushkin museum. In 1981, the museum held the Moscow-Paris exhibition. In 2016, art historians discovered 59 Italian Renaissance sculptures in the Pushkin Museum that had been missing from Berlin's collections since the Second World War.

In March 2022, a number of museums officials, including deputy directors, resigned to protest against Russia's invasion of Ukraine.

Building
The building of the Pushkin State Museum of Fine Arts was designed by Roman Klein and Vladimir Shukhov. Construction lasted from 1898 until early 1912, with Ivan Rerberg heading structural engineering effort on the museum site for the first 12 years.

In 2008, President Dmitri A. Medvedev announced plans for a $177 million restoration. A 22 billion rubles ($670 million) expansion, developed by Norman Foster in collaboration with local architectural firm Mosproject-5, was confirmed in 2009, but became mired in disputes with officials and preservationists and concern grew that it would not be completed on schedule for 2018. After Moscow's chief architect Sergei Kuznetsov issued an ultimatum, demanding that Foster take a more active role in the project and prove his commitment by coming to the Russian capital within a month, Norman Foster's firm resigned from the project in 2013. In 2014, Russian architect Yuri Grigoryan, and his firm Project Meganom, were chosen to take over the project. Grigoryan's design provides new modern buildings and, following the protest of heritage groups who campaigned to save the pre-revolutionary architecture, preserves the historic 1930s gas station near the Pushkin's main building inside a glass structure.

Collection
The holdings of the Pushkin State Museum of Fine Arts currently include around 700,000 paintings, sculptures, drawings, applied works, photographs, and archaeological and animalistic objects.

Painting
The earliest monuments from the museum collection are pieces of Byzantine art: mosaics and icons. The early stage of development of Western European painting is represented by a relatively small collection of Italian Primitives. The hall of early Italian art was opened on October 10, 1924.

Graphic art
The Department of Prints and Drawings was founded in 1924, when the museum received the holdings of the Printing Cabinet of the Moscow Public and Rumyantsev Museum. In 1861, Alexander II made a valuable gift to the Printing Cabinet: the Moscow Public and Rumyantsev Museum received more than 20,000 prints from the Hermitage.

Sculpture
The collection of Western European sculptures includes more than 600 pieces. The museum has expanded its holdings over the years and currently owns artworks from the 6th-21st centuries. The first artifacts presented to the Museum of Fine Arts were sculptures from Mikhail Schekin's collections. After the revolution, the museum received sculptures from nationalized collections.

Collection of decorative art pieces (Department of the Old Masters)
The collection of decorative art pieces from Europe includes around 2,000 items. The earliest are from the Middle Ages, and the set as a whole is very diverse.

Archaeological collection

The Museum of Fine Arts was intended primarily as a museum of classical arts. Ancient artifacts were the core and the main components of its collection, and the Department of Antiquity was one of the three major scientific departments. Its founder and director, Ivan Tsvetaev (1847-1913), was an expert in ancient art, as were his closest associates, Vladimir Malmberg (1860-1921) and Nikolay Scherbakov (1884-1933).

Egypt
Most of the objects presented in Hall No. 1 have been on display since the museum opening in 1912 and come from the collection of Vladimir Golenishchev (1856-1947).

Ancient civilizations
The museum holdings of genuine artifacts of Southwest Asia are based on the collection of Russian Orientalist and Egyptologist Vladimir Golenishchev.

Antiquity
The antique collection of the Pushkin State Museum of Fine Arts includes many genuine artifacts: more than 1,000 vessels, small plastic pieces, and sculptures.

Tsvetaev's collection of casts
The collection of casts and copies, typical for European museums of the nineteenth century, is unique today in its preservation and consistency. With a similar cohesiveness, Tsvetaev wanted to present plastic art of the modern era and complete the collection with casts made from contemporary sculptures, where Auguste Rodin's works would take the central place.

Numismatic collection
Today, the holdings of the Numismatics Department of the Pushkin State Museum of Fine Arts form a collection in excess of 200,000 items and 3,000 volumes of the special library. It was started at Imperial Moscow University. In 1888, the collection was divided and formed the basis for the major numismatic collections of Moscow that belonged to the Historical Museum and the Alexander III Fine Arts Museum.

Since 1912, objects of ancient and Western European numismatics from the university collection were transferred to the Sculpture Department of the Fine Arts Museum and mostly kept packaged. By June 1925, museum custodians had grouped together a number of cases with coins, medals, and casts and created the Numismatic Cabinet located on the balcony of the White Hall. In 1945, the museum's Numismatic Cabinet became an independent department. It includes archaeological material from Central Asia, such as a hoard of Kushano-Sasanian coins acquired in 2002

Museum Quarter
The work on the Museum Quarter of the Pushkin State Museum of Fine Arts started in the late 2000s. In 2019–23, the Main Building of the Pushkin State Museum of Fine Arts will be reconstructed.

Directors
1961-2013: Irina Antonova

2013-March 2023: Marina Loshak

title: Pushkin Museum