Posts Tagged ‘XY’

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Use of sexed semen in conjunction with in vitro embryo production is a potentially efficient means of obtaining offspring of predetermined sex. Sperm sorting is a means of choosing what type of sperm cell is to fertilize the egg cell. It can be used to sort out sperm that are most healthy, as well as determination of more specific traits, such as sex selection in which spermatozoa are separated into X- (female) and Y- (male) chromosome bearing populations based on their difference in DNA content. The resultant ‘sex-sorted’ spermatozoa are then able to be used in conjunction with other assisted reproductive technologies such as artificial insemination or in-vitro fertilization (IVF) to produce offspring of the desired sex. DNA damage in sperm cells may be detected by using Raman spectroscopy.  It is not specific enough to detect individual traits, however. The sperm cells having least DNA damage may subsequently be injected into the egg cell by intracytoplasmic sperm injection (ICSI).

Sperm sorting utilizes the technique of flow cytometry to analyze and ‘sort’ spermatozoa. During the early to mid 1980s, Dr. Glenn Spaulding was the first to sort viable whole human and animal spermatozoa using a flow cytometer, and utilized the sorted motile rabbit sperm for artificial insemination. Subsequently, the first patent application disclosing the method to sort “two viable subpopulations enriched for x- or y- sperm” was filed in April 1987 and the patent included the discovery of haploid expression (sex-associated membrane proteins, or SAM proteins) and the development of monoclonal antibodies to those proteins. Additional applications and methods were added, including antibodies, from 1987 through 1997. At the time of the patent filing, both Lawrence Livermore National Laboratories and the USDA were only sorting fixed sperm nuclei, after the patent filing a new technique was utilized by the USDA where “sperm were briefly sonicated to remove tails”. USDA in conjunction with Lawrence Livermore National Laboratories, ‘Beltsfield Sperm Sexing Technology’ relies on the DNA difference between the X- and Y- chromosomes.

Prior to flow cytometric sorting, semen is labeled with a fluorescent dye called Hoechst 33342 which binds to the DNA of each spermatozoon. As the X chromosome is larger (i.e. has more DNA) than the Y chromosome, the “female” (X-chromosome bearing) spermatozoa will absorb a greater amount of dye than its male (Y-chromosome bearing) counterpart. As a consequence, when exposed to UV light during flow cytometry, X spermatozoa fluoresce brighter than Y- spermatozoa. As the spermatozoa pass through the flow cytometer in single file, each spermatozoon is encased by a single droplet of fluid and assigned an electric charge corresponding to its chromosome status (e.g. X-positive charge, Y-negative charge). The stream of X- and Y- droplets is then separated by means of electrostatic deflection and collected into separate collection tubes for subsequent processing.

While highly accurate, sperm sorting by flow cytometry will not produce two completely separate populations. That is to say, there will always be some “male” sperm among the “female” sperm and vice versa. The exact percentage purity of each population is dependent on the species being sorted and the ‘gates’ which the operator places around the total population visible to the machine. In general, the larger the DNA difference between the X and Y chromosome of a species, the easier it is to produce a highly pure population. In sheep and cattle, purities for each sex will usually remain above 90% depending on ‘gating’, while for humans these may be reduced to 90% and 70% for “female” and “male” spermatozoa, respectively. Some approaches to in vitro fertilization involve mixing sperm and egg in a test tube and letting nature take its course. But in about half of all infertility cases, a problem with the man’s sperm may require a more direct method. In these cases, a different process, called intracytoplasmic sperm injection (ICSI), in which a single sperm cell is injected directly into an egg, is sometimes used. With this one-shot opportunity, it’s important to choose a sperm cell with the best potential for success. A team at the University of Edinburgh, Scotland, has now announced a new technique to ensure that the best sperm win: analyzing their DNA for potential damage beforehand, and choosing those that are structurally sound.

To optimize success rates of IVF, selection of the most viable embryo(s) for transfer has always been essential, as embryos that are cryopreserved are thought to have a reduced chance of implanting after thawing. Recent developments challenge this concept. Evidence is accumulating that all embryos can now be cryopreserved and transferred in subsequent cycles without impairing pregnancy rates or maybe even with an improvement in pregnancy rates. In such a scenario no selection method will ever lead to improved live birth rates, as, by definition, the live birth rate per stimulated IVF cycle can never be improved when all embryos are serially transferred. In fact, selection could then only lower the live birth rate after IVF. The only parameter that could possibly be improved by embryo selection would be time to pregnancy, if embryos with the highest implantation potential are transferred first.

In the majority of human IVF cycles multiple embryos are created after ovarian hyperstimulation. The viability of these embryos, and as a consequence the chance for an embryo to successfully implant, is subject to biological variation. To achieve the best possible live birth rates after IVF while minimizing the risk for multiple pregnancy, one or two embryos that are considered to have the best chance of implanting are selected for transfer. Subsequently, supernumerary embryos with a good chance of implanting are selected for cryopreservation and possible transfer in the future while remaining embryos are discarded.

The best available method for embryo selection is morphological evaluation. On the basis of multiple morphological characteristics at one or several stages of preimplantation development, embryos are selected for transfer. However, with embryo selection based on morphological evaluation implantation rates in general do not exceed 35%, although varying results have been reported. This has resulted in a strong drive for finding alternative selection methods.

The best studied alternative selection method is preimplantation genetic screening (PGS). The classical form of PGS involves the biopsy at Day 3 of embryo development of a single cell of each of the embryos available in an IVF cycle and analysis of this cell by fluorescence in-situhybridization (FISH) for aneuploidies, for a limited number of chromosomes. Only embryos for which the analyzed blastomere is euploid for the chromosomes tested are transferred. Although this method of PGS has been increasingly used in the last decade, recent trials show that it actually decreases ongoing pregnancy rates compared with standard IVF with morphological selection of embryos.

In an effort to overcome some of the drawbacks of PGS using cleavage stage biopsy and FISH, new methods to determine the ploidy status of a single cell are developed, such as comparative genomic hybridization arrays or single nucleotide polymorphism arrays. Furthermore, in an attempt to avoid the confounding effects of chromosomal mosaicism, embryos are now biopsied at either the zygote or blastocyst stage. In addition, increasing time and money are invested in the development of high-tech, non-invasive methods to select the best embryo for transfer in IVF.

This Include metabolomic profiling, amino acid profiling, respiration-rate measurement and birefringence imaging.

  • In metabolomic profiling, spectrophotometric tests are used to measure metabolomic changes in the culture medium of embryos;
  • in proteomic profiling, proteins produced by the embryo and released into the culture medium are identified;
  • in amino acid profiling, amino acid depletion and production by the embryo is assessed using the culture medium;
  • in respiration-rate measurement, the respiration rate of embryos is assessed; and
  • in birefringence imaging, polarization light microscopy is used to assess the meiotic spindle or the zona pellucida.

Embryo donation (also known as embryo adoption) is the compassionate gifting of residual cryopreserved embryos by consenting parents to infertile recipients. At present, only a limited number of such transactions occur. In 2010, the last year for which U.S. data were available, fewer than 1000 embryo donations were recorded. These acts of giving, unencumbered by federal law, are being guided by a limited number of state laws. Moreover, the practice is sanctioned by professional societies, such as the American Society for Reproductive Medicine, subject to the provision that “the selling of embryos per se is ethically unacceptable.” As such, the not-for-profit donation of existing embryos by consenting parents comports with a triad of commonly held ethical attributes. First, donated embryos are not sold for profit. Second, donated embryos are (by original intent) generated for self-use. Third, donated embryos are the product of an unambiguous parental unit and as such are transferable. All told, embryo donation constitutes an established if limited component of present-day assisted reproduction.

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Intersexuality: Management of Patients

Reporter and Curator: Dr. Sudipta Saha, Ph.D.


Humans can be immensely strong and adaptable. Certainly some intersexed individuals can, in dignity, maintain themselves in a manner that they neither would have chosen nor in which they feel comfortable — as have others with a life condition from birth that cannot be changed (from cleft palate to meningomyelocele).

Many can adjust to surgery and reassignment for which they were not consulted and many have learned to accept secrecy, misrepresentations, white and black lies and loneliness. People make life accommodations every day and try to better their lot for tomorrow. Many individuals that have come to terms with their life regardless of how stressed or painful.

However, there are individuals who have been given neonatal surgery for cleft palate or meningomyelocele, many of those who have had genital surgery or been sex reassigned neonatally have complained bitterly of the treatment. Some have sex reassigned themselves. Others treated similarly have reasons not to make an issue of the matter but are living in silent despair but coping.


  • In all cases of ambiguous genitalia, to establish most probable cause, do a complete history and physical. The physical must include careful evaluation of the gonads and the internal as well as external genital structures. Genetic and endocrine evaluations are usually needed and interpretation can require the assistance of a pediatric endocrinologist, radiologist and urologist. Pelvic ultrasonography and genitography may be required. Do not hesitate to seek expert help; a team effort is best. The history must include assessment of the immediate and extended family.Be rapid in this decision making but take as much time as needed. Hospitals should have established House Staff Operating Procedures to be followed in such cases. Many consider this a medical emergency (and in cases of electrolyte imbalance this may be immediately so) nevertheless, it is believed that most doubt should be resolved before a final determination is made. It is simultaneously advised that all births be accompanied by a full genital inspection. Many cases of intersex go undetected.
  • Immediately, and simultaneously with the above, advise parents of the reasons for the delay. Full and honest disclosure is best and counseling must start directly. Insure that the parents understand this condition is a natural variety of intersex that is uncommon or rare but not unheard of. Convey strongly to the parents that they are not at fault for the development and the child can have a full, productive and happy life. Repeat this counseling at the next opportunity and as often as needed.
  • The child’s condition is nothing to be ashamed of but it is also nothing to be broadcast as a hospital curiosity. The child and family confidentiality must be respected.
  • In the most common cases, those of hypospadias and congenital adrenal hyperplasia (C.A.H.) diagnosis should be rapid and clear. In other situations, with a known diagnosis, declare sex based on the most likely outcome for the child involved. Encourage the parents to accept this as best; their desire as to sex of assignment is secondary. The child remains the patient. When assignment is based on the most likely outcome, most children will adapt and accept their gender assignment and it will coincide with their sexual identity.
  • The sex of assignment, when based on the nature of the diagnosis rather than only considering the size or functionality of the phallus, respects the idea that the nervous system involved in adult sexuality has been influenced by genetic and endocrine events that will most likely become manifest with or after puberty. In the majority of cases this sex of assignment will indeed be in concert with the appearance of the genitalia. In certain childhood situations, however, such assignment will be counter to the genital appearance (e.g., for reductase deficiency). The concern is primarily how the individual will develop and prefer to live post puberty when he or she becomes most sexually active.

Rear as male:

XY individuals with Androgen Insensitivity Syndrome (A.I.S.) (Grades 1-3)

XX individuals with Congenital Adrenal Hyperplasia (C.A.H.) with extensively fused labia and a penile clitoris

XY individuals with Hypospadias

Persons with Klinefelter syndrome

XY individuals with Micropenis

XY individuals with 5-alpha or 17-beta reductase deficiency

Rear as female:

XY individuals with Androgen Insensitivity Syndrome (A.I.S.) (Grades 4-7)

XX individuals with Congenital Adrenal Hyperplasia (C.A.H.) with hypertrophied clitoris

XX individuals with Gonadal dysgenesis

XY individuals with Gonadal dysgenesis

Persons with Turner’s syndrome

For those individuals with mixed gonadal dysgenesis (MGD) assign male or female dependent upon the size of the phallus and extent of the labia/scrotum fusion. The genital appearance of individuals with MGD can range from that of a typical Turner’s syndrome to that of a typical male. Evaluation of high male-like testosterone levels in these cases is also rationale for male assignment.

True hermaphrodites should be assigned male or female dependent upon the size of the phallus and extent of the labia/scrotum fusion. If there is a micropenis, assign as male. Admittedly, in some cases a clear diagnosis is not possible, the genital appearance will seem equally male as female and prediction as to future development and gender preference is difficult. There is little evidence a poorly functioning clitoris and vagina is any better than a poorly functioning penis and there is no higher reason to save the reproductive capacity of ovaries over testes. In such difficult cases, whichever decision is made, the likelihood of the individual independently switching gender remains. The medical team in such cases will be taxed to make the best management decision.

  • While sex determination is ongoing, the hospital administration can wait for a final diagnosis before entering a sex of record and Staff can refer to the child as “Infant Jones” or “Baby Brown.” After a sex designation has been made, naming and registration can occur. In those cases mentioned above, where prediction of future outcome is in doubt, parents might consider that a name be used that is appropriate for either males or females (e.g., Lee, Terry, Kim, Francis, Lynn, etc.).
  • Perform no major surgery for cosmetic reasons alone; only for conditions related to physical/medical health. This will entail a great deal of explanation needed for the parents who will want their children to “look normal.” Explain to them that appearances during childhood, while not typical of other children, may be of less importance than functionality and post pubertal erotic sensitivity of the genitalia. Surgery can potentially impair sexual/erotic function. Therefore such surgery, which includes all clitoral surgery and any sex reassignment, should typically wait until puberty or after when the patient is able to give truly informed consent.
  • Major prolonged steroid hormone administration (other than for management of C.A.H.) too should require informed consent. Many intersex or sex reassigned individual’s have felt they were not consulted about their use and effects and regretted the results.
  • In individuals with A.I.S, do not remove gonads for fear of potential tumor growth; such tumors have not been reported to occur in prepubertal children. Retention of the gonads will forestall the need for hormone replacement therapy and possibly help reduce osteoporosis.Furthermore, delaying gonadectomy until after puberty will allow the young woman to come to terms with her diagnosis, understand the reason for her surgery and participate in the decision.
  • Advice regarding gonad removal from true hermaphrodites, individuals with streak gonads and others where malignancies can potentially occur is not so clear. Prophylactically it is common to remove these early; particularly in cases of gonadal dysgenesis.Watchful waiting with frequent checks is always prudent. It is suggested, whenever the gonads are removed, is to explain as best as possible why the procedure is needed and attempt to get consent. If the child is too young to understand the reason for the surgery, its necessity should be explained as early as possible.
  • In rearing, parents must be consistent in seeing their child as either a boy or girl; not neuter. In the society intersex is a designation of medical fact but not yet a commonly accepted social designation. With age and experience, however, an increasing number of hermaphroditic and pseudohermaphroditic individuals are adopting this identification. In any case, advise parents to allow their child free expression as to choices in toy selection, game preference, friend association, future aspirations and so forth.
  • Offer advice and tips on how to meet anticipated situations, e.g., how to deal with grandparents, siblings, baby sitters and others that might question the child’s genital appearance (e.g., “He/she is different but normal. When the child is older he/she and the doctors will do what seems best.”) Parents should minimize the opportunities for such questioning by strangers.
  • Be clear that the child is special and, in some cases might, before or after puberty, accept life as a tomboy or a sissy or even switch gender altogether. The individual may demonstrate androphilic, gynecophilic or ambiphilic orientation. These behaviors are not due to poor parental supervision but will be related to an interaction of the biological, psychological, social and cultural forces to which a child with intersexuality is subject. Some individuals will be quite sexually active and others will be altogether reserved and have little or no interest in sexual relationships.
  • The patient’s special situation will require guidance as to how to meet potential challenges from parents, peers and strangers. He or she will need love and friendly support.Not all parents will be helpful, understanding, or benign and childhood, adolescent, and adult peers can be cruel. Positive peer interaction should be facilitated and encouraged.
  • Maintain contact with family so that counsel is available particularly at crucial times.Counseling should be multi-staged (at birth, and at least again at age two, at school entry, prior to and during pubertal changes, and yearly during adolescence) and it should be detailed and honest. Counseling should be straight-forward, neither patronizing or paternalistic, to parents and to the child as he or she develops with as much full disclosure as the parents and child can absorb. The counseling should ideally be by those trained in sexual/gender/intersex matters.
  • As the child matures there must be opportunity for private counseling sessions and it is essential the door remains open for additional consultation as needed. On the one hand, the full impact of the situation will not always be immediately apparent to the parents or child. On the other hand, they might magnify the developmental potential of the genital ambiguity. As above, the counseling should ideally be by those trained in sexual/gender/intersex matters.
  • Counseling must include developmental sequelae to be anticipated. This should be along medical/biological lines and along social/psychological lines. Do not avoid honest and frank talk of sexual and erotic matters. Discuss the probabilities of puberty such as the presence or absence of menses and the potential for fertility or infertility. Contraception advice may be needed and safe-sex advice is always warranted. Certainly the full gamut of heterosexual, homosexual, bisexual and even celibate options –however these are interpreted by the patient– must be offered and candidly discussed. Adoption possibilities can be broached for those that will be infertile. It is better to discuss these issues early rather than late. Do not obfuscate; knowledge is power enabling the individuals to structure their lives accordingly.
  • The family should be encouraged to openly discuss the situation among themselves, with and without a counselor present, so the child and parents can honestly come to terms with whatever the future holds. Parents have to understand their child’s needs and feelings and the child has to understand the concerns of the parents.
  • As early as possible put the family in touch with a support group. There are such groups for individuals with Androgen Insensitivity Syndrome, Congenital Adrenal Hyperplasia, Klinefelter Syndrome, and Turner’s Syndrome. Intersexed individuals as a whole (hermaphrodites and pseudohermaphrodites of all etiologies) have a support group, the Intersex Society of North America [addresses for these groups are listed below]. It is emphasized that one on one contact with another person having similar experiences can be the most uplifting factor in an intersexed person’s healthy development! Individual groups or chapters might be more inclined toward parental concerns while others might be tilted toward the intersexed person’s concerns. Both perspectives are needed and separate meetings for each faction are useful. Parents need to talk about their feelings in an environment free of intersexed children and adults and the intersexed children and adults similarly need to be able to discuss their feelings and concerns free of their parents. There are times when it is appropriate for physicians to be present and times when it is not.
  • Keep genital inspection to a minimum and request permission for inspection even from a child. Hold in mind that a child may not feel able to deny a physician’s request even though that might be his/her wish. The individuals must come to realize that their genitals are their own and they, not the doctors, parents or anyone else, have control over them. Allow others to view the patient only with his or her permission. Often the genital inspections themselves become traumatic events.
  • Let the child grow and develop as normally as possible with a minimum of interference other than needed for medical care and counseling. Let him/her know that help is available if needed. Listen to the patient; even when as a child. The physician should be seen as a friend.
  • With increasing maturity the designation of intersex may be acceptable to some and not to others. It should be offered as an optional identity along with male and female.
  • As puberty approaches be open and honest with the endocrine and surgical options and life choices available. Be candid at the sexual/erotic and other trade-offs involved with surgery or gender change and insure that any decision finally be that of the fully informed individual regardless of age. To have him/her discuss the treatment with someone who has undergone the procedure is ideal.
  • Most individuals are convinced by the age of 10-15 as to the direction that would be most suitable for them; male or female. Some decisions, however, should be stalled as long as possible to increase the likelihood that the individual has some experience with which to judge. For instance, a female with a phallic clitoris, sexually inexperienced with partner or masturbation, may not realize the loss in genital sensitivity and responsivity that can accompany cosmetic clitoral reduction. Insure that sufficient information is provided to aid in any decision.
  • Most intersex conditions can remain without any surgery at all. A woman with a phallus can enjoy her hypertrophied clitoris and so can her partner. Women with the androgen insensitivity syndrome or virilizing congenital adrenal hyperplasia who have smaller than usual vaginas can be advised to use pressure dilation to fashion one to facilitate coitus; a woman with partial A.I.S. likewise can enjoy a large clitoris. A male with hypospadias might have to sit to urinate without mishap but can function sexually without surgery. An individual with a micropenis can satisfy a partner and father children.There is disagreement as to whether gonads that might prove masculinizing or feminizing at puberty should be removed early on to prevent such changes in a child that does not desire such changes. The disagreement involves the concept that the individual faced with such changes might actually come to prefer them to the habitus of rearing but will only become aware of them post hoc. The bias is to leave them in so any genetic-endocrine predisposition imposed prenatally can come to be activated with puberty. It is admitted that however there is no good body of clinical data from which the best prognosis can be made in such cases. There are some indications, however, that even without the gonads the adrenals might prod pubertal changes.
  • If a gender change is being considered, have the individual experience a real-life living test. In this way the individual will have first hand experience in how it actually is to live in the other role. Experience has shown that most indeed make the switch permanent but some return to their original sex of rearing. Some, usually as adults, will accept an identity as an intersex and plot their own course.
  • Maintain accurate medical, surgical, and psychotherapy records of all aspects of each case. This will facilitate whatever treatment is needed and assist in future research to enhance management of subsequent intersex cases. These records should be available to the patient.
  • Whenever possible, long term follow-up evaluations, e.g., at 5, 10, 15, and even 20 years of age, should become part of the record.
  • Last, it is believed that information and advice may be provided as much as possible but not to be “authoritarian” in the actions. The postpubertal individual must be allowed time to consider, reflect, discuss and evaluate and then, have the last word in his or her genital modification and gender role and final sex assignment.


European Congress of Endocrinology 2008

Berlin, Germany
03 May 2008 – 07 May 2008
European Society of Endocrinology

Hypospadias and micropenis in congenital adrenal hyperplasia: a case study

Sandra Fleischer, Ute S Groß, Hjördis HS Drexler, Achim Wüsthof & Heinrich M Schulte

Endokrinologikum Hamburg, Hamburg, Germany.

Introduction: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases with increased adrenal androgens secretion from the adrenal cortex, characterized by simple virilizing and salt wasting forms. Deficiency of 21-hydroxylase, caused by mutations in the 21-hydroxylase gene (CYP21A2) is the most frequent CAH, accounting for more than 90 percent of CAH cases. Deficiency of 3 beta-Hydroxysteroid-Dehydrogenase Type II is caused by mutations in the HSD3B2 gene and accounts for about 1–10 percent of cases of CAH.

Patient: This report is about a 2-year-old patient of Turkish origin referred to our center with clinical finding of penoscrotal hypospadias and micropenis (stretched penile length 1.5 cm). Testicles were palpable bilaterally in the scrotum. Due to initial biochemical and hormonal findings moleculargentic analysis of CYP21A2 gene was already done, showing heterozygous germline mutations p.Val281Leu, p.Leu307fs, p.Gln318Stop and p.Arg356Trp. His parents are cousin-german to each other.

Methods: Genomic DNA was extracted from peripheral blood leukocytes. Coding regions and corresponding exon-intron boundaries of the CYP21A2 gene and the HSD3B2 gene were amplified by PCR and subjected to direct sequencing.

Results: A compound heterozygous state of these mutations was excluded by sequencing analysis ofCYP21A2 genes of both parents (father has no mutation). Further hormonal studies suggested a 3 β-Hydroxysteroid dehydrogenase type II deficiency and justified sequence analysis of the HSD3B2 gene. A novel homozygous germline mutation (p.Trp355Arg) was found, for which both parents are heterozygous carriers.

Conclusion: To judge a case of CAH in the right way it is important to look at all clinical aspects in a differentiated way. Comprehensive (clinical, biochemical, hormonal) analysis should be conducted and approved by moleculargenetic analysis in line with a genetic counseling.





Endocrine Abstracts (2008) 16 P589

References on Ethics and Treatment Options:

  1. ^ David A. Warrell (2005). Oxford textbook of medicine: Sections 18-33. Oxford University Press. pp. 261–. ISBN 978-0-19-856978-7. Retrieved 14 June 2010.
  2. ^ Aubrey Milunsky; Jeff Milunsky (29 January 2010). Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment. John Wiley and Sons. pp. 600–. ISBN 978-1-4051-9087-9. Retrieved 14 June 2010.
  3. ^ Richard D. McAnulty, M. Michele Burnette (2006) Sex and sexuality, Volume 1Greenwood Publishing Group, p.165
  4. ^ Elton, Catherine (2010-06-18). “A Prenatal Treatment Raises Questions of Medical Ethics”TIME. Retrieved 2010-07-05.
  5. ^ Dreger, Alice; Ellen K. Feder, Anne Tamar-Mattis (2010-06-29). “Preventing Homosexuality (and Uppity Women) in the Womb?”. Bioethics Forum, a service of the Hastings Center. Retrieved 2010-07-05.
  6. ^ Dreger, Alice; Ellen K. Feder, Anne Tamar-Mattis (30 July 2012). “Prenatal Dexamethasone for Congenital Adrenal Hyperplasia”Journal of Bioethical Inquiry. Retrieved 3 August 2012.
  7. ^ Fernández-Balsells, M.M.; K. Muthusamy, G. Smushkin, et al (2010). “Prenatal dexamethasone use for the prevention of virilization in pregnancies at risk for classical congenital adrenal hyperplasia because of 21-hydroxylase (CYP21A2) deficiency: A systematic review and meta-analyses”Clinical Endocrinology 73 (4): 436–444. Retrieved 3 August 2012.
  8. ^ Bongiovanni, Alfred M.; Root, Allen W. (1963). “The Adrenogenital Syndrome”. New England Journal of Medicine 268 (23): 1283.doi:10.1056/NEJM196306062682308.

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Human sex refers to the processes by which an individual becomes either a male or female during development. Complex mechanisms are responsible for male sex determination and differentiation. The steps of formation of the testes are dependent on a series of Y-linked, X-linked and autosomal genes actions and interactions. After formation of testes the gonads secrete hormones, which are essential for the formation of the male genitalia. Hormones are transcription regulators, which function by specific receptors. Ambiguous genitalia are result of disruption of genetic interaction. This review describes the mechanisms, which lead to differentiation of male sex and ways by which the determination and differentiation may be interrupted by naturally occurring mutations, causing different syndromes and diseases.


Sex determination: Initial event that determines whether the gonads will develop as testes or ovaries. Sex is determined by “the heat of the male partner during intercourse” –Aristotle (335 B.C.). Today: both environmental and internal mechanisms of sex determination can operate in different species.


Sex differentiation: Subsequent events that ultimately produce either the male or female sexual phenotype. Sexual differentiation is conformed in the human during four successive steps: the constitution of the genetic sex, the differentiation of the gonads, the differentiation of the internal and the external genital tractus and the differentiation of the brain and the hypothalamus.

Sex determination, which depends on the sex-chromosome complement of the embryo, is established by multiple molecular events that direct the development of germ cells, their migration to the urogenital ridge, and the formation of either a testis, in the presence of the Y chromosome (46, XY), or an ovary in the absence of the Y chromosome and the presence of a second X chromosome (46, XX). Sex determination sets the stage for sex differentiation, the sex-specific response of tissues to hormones produced by the gonads after they have differentiated in a male or female pattern. A number of genes have been discovered that contribute both early and late to the process of sex determination and differentiation. In many cases our knowledge has derived from studies of either spontaneous or engineered mouse mutations that cause phenotypes similar to those in humans. How mutations in these genes cause important clinical syndromes and the clinical entities that continue to elude classification at the molecular level have to be tested. Knowledge of the molecular basis of disorders of sex determination and differentiation pathways will continue to have a strong influence on the diagnosis and management of these conditions.

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Disorders of sex development include many different medical conditions. They could happen to anyone, and are actually more common than you might think. You may have heard DSD called terms such as “intersex” or “hermaphrodite” or “pseudohermaphroditism.” However, a meeting of international experts reached consensus that the term “disorders of sex development” should replace those terms. Because there are so many stages of sex development in human life, there are a lot of opportunities for a person to develop along a path that is not the average one for a boy or a girl. When a less-common path of sex development is taken, the condition is often called a “disorder of sex development” or DSD. So DSD is a name given to a lot of different variations of sex development.

These conditions have specific names, and include:

  • 46,XX congenital adrenal hyperplasia (CAH)
  • Testosterone biosynthetic defects
  • Androgen insensitivity syndrome (AIS)—can be partial (PAIS) or complete (CAIS)
  • Gonadal dysgenesis (partial and complete)
  • Swyer syndrome (46,XY gonadal dysgenesis)
  • 5-alpha reductase deficiency (5-AR deficiency)
  • 46,XY micropenis
  • Klinefelter syndrome (47,XXY)
  • Turner syndrome (45,X)
  • Hypospadias
  • Epispadias
  • Mayer-Rokitansky-Kuster-Hauser syndrome (Also called MRKH, Müllerian agenesis and vaginal agenesis)
  • Sex-chromosome mosaicism (for example mixed gonadal dysgenesis (45,X/46,XY; sometimes referred to as XY Turners)
  • 46,XX/46,XY (chimeric, ovotesticular DSD)
  • Persistant Müllerian duct syndrome
  • Kallman syndrome
  • 17-beta reductase deficiency (XX or XY)
  • 46,XY 3-beta-hydroxysteroid dehydrogenase deficiency (HSD deficiency)
  • Aphallia
  • Clitoromegaly
  • 46,XY cloacal exstrophy
  • Progestin-induced virilization

The symptoms associated with intersex will depend on the underlying cause, but may include:

  • Ambiguous genitalia at birth
  • Micropenis
  • Clitoromegaly (an enlarged clitoris)
  • Partial labial fusion
  • Apparently undescended testes (which may turn out to be ovaries) in boys
  • Labial or inguinal (groin) masses — which may turn out to be testes — in girls
  • Hypospadias [the opening of the penis is somewhere other than at the tip; in females, the urethra (urine canal) opens into the vagina]
  • Otherwise unusual appearing genitalia at birth
  • Electrolyte abnormalities
  • Delayed or absent puberty
  • Unexpected changes at puberty

Disorders of sex development (DSD) with or without ambiguous genitalia require medical attention to reach a definite diagnosis. Advances in identification of molecular causes of abnormal sex, heightened awareness of ethical issues and this necessitated a re-evaluation of nomenclature. The term DSD was proposed for congenital conditions in which chromosomal, gonadal or anatomical sex is atypical. In general, factors influencing sex determination are transcriptional regulators, whereas factors important for sex differentiation are secreted hormones and their receptors.The current intense debate on the management of patients with intersexuality and related conditions focus on four major issues: 1) aetiological diagnosis, 2) assignment of gender, 3) indication for and timing of genital surgery, 4) the disclosure of medical information to the patient and his/her parents. The psychological and social implications of gender assignment require a multidisciplinary approach and a team which includes ageneticist, neonatologist, endocrinologist, gynaecologist, psychiatrist, surgeon and a social worker. Each patient should be evaluated individually by multidisciplinary approach.

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