Androgen Resistance Syndromes - Essay Example

? Androgen Resistance Syndromes Androgen Resistance Syndromes Introduction Clinical syndrome of resistance to androgens (the male hormone) in human beings has been recorded for more than two hundred years. The symptom includes female appearance with both vagina and testes but without uterus, fallopian tubes or ovaries (Definition of Androgen 2011). The external genitalia may appear normal but the vagina is not present or undeveloped and absence of uterus (Bakan 1985, cited in Oakes et al. 2008). The physical symptoms may vary from person to person. Resistance to androgens syndrome is also commonly known as Androgen Insensitivity Syndrome of AIS (Hughes & Deeb 2006) or Testicular feminisation (Androgen Insensitivity Syndrome 2011). Androgen Resistance (AR) syndrome is rooted in the genes of the affected individual. AIS is inherited as a “recessive X-linked single gene syndrome” that may appear in a different form in the children of the same parents (Evans 1997, cited in Diamond & Watson 2009, para. 8). Thus, the parents may raise one child as a boy and another as a girl (Evans 1997, cited in Diamond & Watson 2009). A United Kingdom AIS study on persons 16 years old or younger revealed that 59 percent of those with PAIS condition were determined as males (Viner et al. 1997, cited in Diamond & Watson 2009). However, majority of studies published with clinical-psychiatric engagement refer to persons treated and reared as females (Evans 1997, cited in Diamond & Watson 2009). Studies show that around 20 percent of girls with inguinal hernia have AIS (Androgen Insensitivity Syndrome, OII 2011). Around 30 to 50 percent of those with PAIS and some of those with CAIS have dissimilar metabolic process (Androgen Insensitivity Syndrome, OII 2011). With the syndrome originating from the mutation of genes and inherited from the parents, the condition is lifetime and cannot be altered. Therapy and treatment should be continuous and multi-disciplinary. The impact though is much on the psychological aspect of the person affected, which involve the person’s view upon himself or herself and society’s treatment. Epidemiology AIS is caused by a number of genetic flaw of X chromosome that makes the body incapable of responding to the hormone that produces the male physique (Androgen Insensitivity Syndrome 2011). It is classified as Complete AIS (CAIS) and Incomplete AIS (IAIS) (Androgen Insensitivity Syndrome 2011). CAIS hinders the growth of penis and other male characteristics, and appears to be a female (Androgen Insensitivity Syndrome 2011). It occurs in one for every 20,000 live births (Androgen Insensitivity Syndrome 2011). The incomplete form (IAIS) has varied sexual ambiguities and includes the infertile male syndrome (associated with androgen receptor disorder) and the Reifenstein syndrome (also Gilbert-Dreyfus syndrome or Lubs syndrome), a condition connected with breast growth in males, inability of one or both testes to move down into the scrotum after birth, and hypospadias (i.e. the urethra opening of the urethra is located under the penis instead of the tip) (Androgen Insensitivity Syndrome 2011). Figure 1 Graded Clinical Classification of AIS (Source: Quigley et al. 1995, cited in Diamond & Watson 2009) Quigley et al. (1995) has provided a clear depiction of AIS syndrome as shown in Figure 1. They graded the classification from 1 to 7 with increasing severity or “more defective masculini(s)ation” as follows – “a) grade 1: normal masculini(s)ation in utero, b) grade 2: male phenotype with mild defect in masculini(s)ation (e.g. isolated hypospadias), c) grade 3: male phenotype with severe defect in masculini(s)ation—small penis, perineoscrotal hypospadias, bifid scrotum or cryptorchidism, d) grade 4: severe genital ambiguity – clitoral-like phallus, labioscrotal folds, single perineal orifice, e) grade 5: female phenotype with posterior labial fusion and clitoromegaly, and f) grade 6/7: female phenotype (grade 6 if pubic hair present in adulthood, grade 7 if no pubic hair in adulthood)” (Quigley et al. 1995, cited in Diamond & Watson 2009, para. 6). Signs and symptoms In complete AIS, the individual has the female physical form but without a uterus (Androgen Insensitivity Syndrome 2011). The person also has very minimal armpit and pubic hair (Androgen Insensitivity Syndrome 2011). During pubertal stage, the person develops female breasts but does not menstruate (Androgen Insensitivity Syndrome 2011). In Incomplete AIS, the affected person may develop male and female physiological characteristics (Androgen Insensitivity Syndrome 2011). The outer lips of the vagina are partially closed with clitoris enlarged and a shorter vagina (Androgen Insensitivity Syndrome 2011). The following may be present: vagina without cervix or uterus, inguinal hernia with testis (possibly felt during physical examination), normal development of female breasts, presence of testes in the abdomen or unlikely location in the body (Androgen Insensitivity Syndrome 2011), female body form and infertility, tallness, lack of menstrual period, menarche delay, primary amenorrhea, normal female breast development, genetic male XY chromosomes, normal female external genitalia, female voice, ovaries or fallopian tubes or uterus absent, testes hidden in the abdomen or present in the labia, low estrogen level, internal vagina is short, males develop female breasts, development of female breasts in males, minimal axillary hair, female sexual characteristics, minimal pubic hair, and presence of both male and female genitalia (Symptoms of Androgen 2011). Pathophysiology Pathophysiology refers to the study of the physical, genetic and biochemical functions of a disease, abnormal syndrome or disturbance in bodily functions. In AIS, the physical manifestation is rooted on the genetic malfunction of the AR. Usually, CAIS patients are treated as females since they appear as such during birth, and unless there is some suspicion of AIS in the immediate family or inguinal testes have been identified, detection occurs only during puberty (Diamond & Watson 2009). CAIS patients have short vagina, “blind-ending”, and can be elongated or not (Quigley et al. 1992, cited in Diamond & Watson 2009, para. 7). Although the breasts develop, the pubic and axillary hair is scant or totally absent (Diamond & Watson 2009). A remedy is sought when the person fails to menstruate (Diamond & Watson 2009). PAIS individuals are readily noticeable at birth or soon after (Diamond & Watson 2009). The child is treated and reared as boy or a girl depending on the “degree of masculini(s)ation of the genitals” (Diamond & Watson 2009, para. 7). In genetic male, the gonadotropins and testosterone are normal but the physiological response of androgen in the concerned organs is lessened or totally absent (Balducci et al. 1996). Gonadotropins are protein hormones responsible for sexual development and normal reproductive functioning. Testosterone is a male hormone that promotes the development of the testis, prostrate and other male physiological characteristics. Two anomalies existent androgen target tissues in this condition are: a) malfunctioning metabolism of the testosterone called the 5-alpha reductase type 2 deficiency, and b) androgen receptors defect, otherwise known as the androgen insensitivity syndrome (AIS) (Balducci et al. 1996). As a result, the subject may grow female external genitalia and impaired growth of masculine physiology (Balducci et al. 1996). The condition of the subject is either referred to as complete form of AIS (CAIS) (where the feminine phenotype is dominant) and the partial form (PAIS) (where the phenotype among subjects is greatly variable) (Balducci et al. 1996). To determine the appropriate sexual assignation and diagnosis of the subject, a wide array of tests is necessary that encompasses hormonal, genetic and molecular analysis (Balducci et al. 1996). It was reported that the defect in the AIS occurs during the cloning of cDNA that involves the “polymerase chain reaction, denaturing gradient gel electrophoresis, and nucleotide sequencing” (Balducci et al. 1996, p. 205). The condition with “normal or almost normal testes” but with “female or intersexual genital development” is male pseudohermaphrodism (Balducci et al. 1996, p. 205). The gonadal ridge takes the form of a testes beginning six weeks of gestation through the action DNA-binding protein transcription factor encoded on the shorter arm of the Y chromosome (the region SRY gene that determines sex) (Sinclair et al. 1990, cited in Balducci et al. 1996). The number of genes that affect testis determination is not known (Balducci et al. 1996), but some have been identified. One such gene, called DSS or dosage-sensitive sex reversal, located on the short arm of the X chromosome, affects testis determination if it appears in duplicate (Bordoni 1994, cited in Balducci et al. 1996). This was discovered in the studies conducted with 46 XY females where the distal part of Xp21 was in duplicate (Bordoni 1994, cited in Balducci et al. 1996). In other researches with sexual anomaly patients, the Wilms tumor repressor gene or WT1 (identified in Denys-Drash and WAGR syndromes) and the campomelic dwarfism gene called SOX-9 also determine testis cascade (Pellettier et al. 1991; Wagner et al. 1994, cited in Balducci et al. 1996). The orphan nuclear receptor SF-1 is the recent discovery to have shown to affect gonadal and adrenal differentiation, and also to adjust the manufacture of anti-Mullerian hormone (AMH) and androgens in utero (Shen et al. 1994, cited in Balducci et al. 1996). The Sertoli cells in the testis secrete the glycoprotein AMH from six to eight weeks of gestation, which regress the Mullerian ducts and in the process repress the growth of internal female genitalia (Balducci et al. 1996). The androgen receptor and the androgens initiate “male sex differentiation and development of the male phenotype” (Balducci et al. 1996, p. 206). Testosterone (T) mediates the differentiation of the Wolffian ducts from 9 to 13 weeks of gestation (Balducci et al. 1996). The growth of the male external genitalia, prostate and prostatic urethra during the same period (9 and 13 weeks) need the action of a stronger androgen – dihydrotestosterone (DHT) (Balducci et al. 1996). The enzyme accountable for the transformation of T to DHT (5-alpha reductase type 2) exists in the urogenital tubercles before the latter’s differentiation into external genitalia (Imperato-McGinley et al. 1992; Wilson et al. 1993, cited in Balducci et al. 1996). The enzyme though is not expressed in the Wolffian ducts pending 13 weeks of gestation when differentiation has started (Imperato-McGinley et al. 1992; Wilson et al. 1993, cited in Balducci et al. 1996). Genetic of Androgen Receptor The Androgen Receptor (AR) is a transcription element that can initiate molecular activities that leads to the activation of the gene needed to develop male sexuality (Poujol et al. 2002). Encoded in the X chromosome, AR mediates the activities of androgens during sexual development (McPhaul 2002). The AR gene is located on the long (q) arm of the X chromosome (position 12), specifically on base pair 66,763,873 to base pair 66,944,118 (see Figure 2) (AR 2011). The presence of multiple mutations of the AR genes in AR patients points to the critical function of the nuclear receptor (Gottlieb et al. 2001, cited in Poujol et al. 2002). The variety of male pseudohermaphroditisms ranges from CAIS that gives a female phenotype to PAIS with men being infertile (Poujol et al. 2002). The flaws existing in the AR protein can cause varied anomalies in the development of the male sexuality (McPhaul 2002). Mutations in the AR gene have been found in researches on subjects affected by AIS (McPhaul 2002). AR defects hinder sexual development of internal and external physiologic structures in 46 XY persons (Brinkmann et al. 1996) Figure 2 Location of Androgene Receptor Gene (Source: AR 2011). Genetic alterations have been reported to cause defect that interrupt “AR open-reading frame” (McPhaul 2002, p. 61). This defect is connected with the CAIS phenotype (McPhaul 2002). On the other hand, a mutation that makes single amino acid substitutions in the receptor is specific to DNA-binding or ligand-binding domains and which is connected with several phenotypes of AIS (McPhaul 2002). The presence of AR mutations along with phenotype anomalies led to the consideration of association between mutation and phenotype (McPhaul 2002). Figure 3 Amino Acid Substitutions in DNA-binding Domain Due to Mutations (Source: Quigley et al. 1995; Patterson et al. 1994, cited in Brinkmann et al. 1996) Point mutations in exons 2 and 3 and two deletions of a codon in the AR gene of CAIS and PAIS persons causes amino acid substitutions in DNA-binding domain (Figure 3) (Quigley et al. 1995; Patterson et al. 1994, cited in Brinkmann et al. 1996). The Androgen Receptor belongs to the nuclear receptor superfamily consists of “receptors for steroids and thyroid hormones, vitamin D3 and retinoic acids, and numerous orphan receptors” with no ligand identified yet (Mangelsdorf et al. 1995, cited in Poujol et al. 2002). The receptor can perform various functions in different domains that include “ligand binding, dimerization, DNA binding, and trans-activation” (Poujol et al. 2002). Through hormone binding, the receptor is induced to transconform and translocate into the nucleus where it initialises transcription as it interacts with the transcription system (Poujol et al. 2002). Figure 4 Androgen Receptor Mutations in CAIS and PAIS (Source: Brinkmann et al. 1996). The above diagram shows AR mutations found in Rotterdam in patients affected with CAIS and PAIS conditions. Amino acid residues are depicted as one-letter symbols (Brinkmann et al. 1996). Diagnosis and Management AIS is the common initial diagnosis if a female has no uterus, has testes or ambiguous genitalia (Androgen Insensitivity Syndrome, OII 2011). AIS can be diagnosed in any one of the three stages of life: a) during childhood when hernia is detected or anomalous genitalia is found, b) during adolescence when menstruation does not start, and c) during adulthood when the medical history is traced and the lies and half-truths are uncovered (Obtaining/Facing Diagnosis 2011). The initial test that can be undertaken is for the determination of the XY sex chromosomes which can be done through the buccal (mouth) smear or blood test (i.e. karyotype test to determine chromosomal shape) (Obtaining/Facing Diagnosis 2011). A new chromosomal test in UK mentioned by genetic expert Ieuan Hughes is the Fluoro In Situ Hybridisation (FISH) that shows the X chromosome as green and Y chromosome as red (Obtaining/Facing Diagnosis 2011). AIS can be known with high testosterone level in the blood for a longer time but without remarkable virilisation, and can be confirmed by molecular genetics (Androgen Insensitivity Syndrome, OII 2011). Complete determination of the condition may include the following tests: blood test (for karyotype determination, level of hormones), urine test (can determine 5-alpha reductase), imaging (pelvis ultrasound to image uterus and ovaries, groin ultrasound for testes, to verify presence or nonexistence of internal Mullerian structures, etc.), examination under anaesthesia (if more information is needed which imaging cannot answer, includes laparoscopy), genital skin biopsy (for DNA test), gonadal biopsy (done after testes removal, rarely done unless true hermaphrodite is sought), gonadal histology (histological analysis at the cellular level of the gonads removed), DNA studies (commonly through blood, determine faulty gene among family members), Anti-Mullerian Hormone (AMH) or Mullerian Inhibitory Factor (MIF) (effective marker for presence of testes), familial analysis (around 33 to 30 percent of cases are spontaneous mutations but the rest are inherited through the maternal lineage), prenatal diagnosis (diagnosis possible from 9 to 12 weeks of intrauterine life through chorionic villus sampling, ultrasound and amniocentesis can be used during the 16th week), etc. The infant can be physically examined through the use of a sterile Q-tip into the vagina if inguinal hernia is determined (anaesthesia may be used to lessen anxiety) (Oakes et al. 2008). Karyotyping (in cases of female with hernia) (Sarpel 2005; Hughes & Deeb 2006, cited in Oakes et al. 2008) and imaging (for internal anatomy) are recommended for female CAIS patients (Oakes et al. 2008). Adolescent CAIS patients can undergo hormone testing to determine testosterone and estradiol levels, which may be followed by karyotyping (Oakes et al. 2008). The Androgen Insensitivity Syndrome is a complex condition rooted on the genetic and molecular level mutation that affects the social and psychological aspects of a person. Due to the inability of the person to produce the appropriate hormones responsible for the development of the male phenotype, the patient also suffers from hormone deficiencies. Koch (2011) suggested two aspects in providing medical care for the patient – hormone replacement therapy or HRT and giving psychological support. He said that HRT should first be undertaken for both CAIS and majority of PAIS patients which includes gonadectomy at an appropriate time during the treatment process (Koch 2011). Hormone should be administered for adolescent and adult patients (Koch 2011). Women CAIS patients usually require replacement of estrogen despite them having no uterus (Koch 2011). Although progesterone therapy is still under scrutiny and debate, evidence has shown that this will lessen the risk of breast cancer (Koch 2011). Another study though has shown that administration of progesterone to patients without a uterus may produce scant or no benefit at all (Koch 2011). Thus, estrogen is suggested to be given at low dose and increased with adults (Koch 2011). Estrogen is augmented with progesterone if necessary after the former therapy has been maintained (Koch 2011). For PAIS patients, the traditional treatment is similar to the CAIS regimen (Koch 2011). PAIS subjects with male phenotype can receive testosterone and dihydrotestosterone (DHT) together or without the other testosterone (Koch 2011). DHT is said to be beneficial since it cannot be “aromatici(s)ed to estrogen” (Koch 2011, para. 4). It is suggested that individuals with Kennedy disease cannot undergo testosterone-DHT treatment (Koch 2011). Laboratory testosterone replacement tests have been conducted and have shown neurological effect upon animals, but no confirmation yet as to human subjects (Koch 2011). According to Koch (2011), psychological support may be more important for the patient in the process of treatment. When the patient is still in the infancy stage, the parents are the main clients who must be counselled of possible subsequent recurrence (25 percent of every succeeding pregnancy) (Koch 2011). They must receive genetic counselling and know the potential carrier (Koch 2011). They should also receive continuing family counselling from pediatric or adolescent psychiatrist to help them cope up with the condition of the child, proper manner of informing the affected child, and other related concerns (Koch 2011). If the affected person is an older child, he or she is the primary client (Koch 2011). They can receive advise from pediatric psychologists or child and adolescent psychiatrists who are the clinicians better to manage the medical, psychological and emotional aspects of the person (Koch 2011). The therapy should be long-term since new concerns will come up at the child grows up (Koch 2011). The medical care process has been criticised for lack of emotional and psychological ingredient in the treatment of adult AIS and intersex patients (Koch 2011). The care of the child must be coordinated by the primary health care practitioner with various experts (e.g. geneticist, endocrinologist, surgeons) during the treatment process (Koch 2011). Management should likewise consider the risk to osteoporosis in the longer-term (Stanhope 2010), “decisions on sex assignment, timing of gonadectomy in relation to tumour risk, and genetic and psychological counseling” (Hughes & Deeb 2006, p. 577). According to Diamond and Watson (2009), greater than the medical concern of the patient is the psychological concern the syndrome carries and the management of related psychological problems. Not a few complained that they were not informed of the condition although they had undergone several physical examinations (Diamond & Watson 2009). They only found out the condition on their own and later sought medical help for clarification (Diamond & Watson 2009). The concerns, whether the condition is CAIS or PAIS, may include keeping the condition secret, the time the diagnosis is determined, and the level of open communication among the patient, the parents and the doctor (Diamond & Watson 2009). Part of the management is the ability of the patient to express his or her feelings and thoughts about oneself (Diamond & Watson 2009). Conclusion An individual affected by whatever form of Androgen Insensitivity Syndrome is placed in an anomalous sexual situation wherein there is the presence of both male and female physical and physiological characteristics. This condition puts the person in a psychological dilemma making him or her undecided whether to act and think as a male or a female. The person might also suffer from societal stigma, especially in some societies, when such person previously known to be a female (due to his/her physique) is discovered to also possess male genitalia. He or she may also be the subject of ridicule or exploitation of others. On the part of the person, he or she is constantly plagued by thoughts of shame, indifference, isolation, etc. caused by the situation. In the study by Kessler (1998, cited in Diamond & Watson 2009, para. 11) the AIS respondents revealed that their “most difficulties . . . are connected to secrecy, shame, and stigma.” They may also undergo identity crisis (Diamond & Watson 2009). Persons with AIS should receive long-term medical and psychological treatments so that they will be able to live normally despite the anomalous physiological condition. The government and concerned civic groups should work hand in hand to educate the people and society at large so that AIS individuals should not be stigmatised and ridiculed, but instead be treated humanely. Public health facilities should also reach out to the affected persons, since more often, they would rather live in secrecy than come out in the open to be ridiculed. In this manner, earlier detection can be had and appropriate remedies given, and lessen associated risks to breast cancer or osteoporosis. References Androgen Insensitivity Syndrome. 2011. 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