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Normal and Abnormal Sexual Differentiation

The words, "It's a boy" and "It's a girl" can be heard every hour of every day all around the world. But how distressing it must be when the birth attendants are unable to make such a clear pronouncement? Ambiguous genitalia occur in about one in every 2,000 births and is usually unanticipated and can be a difficult experience for all concerned. What causes ambiguous genitalia? What can be done to correct it? The following information has been developed to answer such questions.

What happens under normal conditions?

The development of the human embryo into a male or female is a complex process that is both dynamic and sequential. Interference with this highly ordered process at any step could result in abnormal sexual differentiation.

At the moment of conception, the mother imparts an X (female) chromosome and the father an X or Y (male) chromosome, creating either an XX (female) or XY (male) embryo. Despite this immediate definition of genetic sex, male and female embryos are identical with respect to internal and external genitalia until the seventh or eighth week of pregnancy. In these early weeks, embryos have two gonads – undefined organs that, during the pregnancy, will develop into testicles or ovaries based on whether the embryo carries the Y chromosome. This chromosome carries the gene responsible for testicle formation, and it is the secretion of testosterone that determines how internal and external genitalia will develop.

Young embryos at this stage also have both male and female internal genital structures. Depending on secretion of testosterone, one set of internal structures will regress, becoming either distinctly male (prostate and vas deferens) or distinctly female (uterus, fallopian tubes and vagina). It is important to note that it is the absence of the male hormones – rather than the presence of female ones – which causes the external and internal genitalia to become female. By the end of the first trimester, embryos can be recognized as having male or female external genitalia. The formation of the internal and external genitalia is called sexual differentiation.

What are some of the processes involved with sexual differentiation?

Gonadal sexual determination: In 1921, it was shown that humans have X- and Y-chromosomes. But it was not demonstrated until the 1950s that the Y chromosome specified development of the testicle.

Over the past 50 years, there has been an intense search to identify the testicle-determining gene, which, in essence, flips the developmental switch for a gonad to develop into a testicle. In 1990, Sinclair and his group discovered a small genetic sequence on the Y chromosome that they believed represented the testicle-determining factor. This gene, called SRY (for sex determining region-Y gene), has now been scientifically demonstrated to be the testicle-determining factor. There also appear to be other genes that are important in the process of sexual differentiation. They appear to act as a series of sequential switches to turn on cellular processes, resulting in development of a testicle or ovary. 

Chromosomal sex determination: During the first six weeks of an embryo's development, the cells that develop into gonads, internal ducts and external genitalia have the potential to become male or female and are therefore called "bipotential." In the presence of SRY, the bipotential gonad develops into a testicle, which becomes apparent at six to seven weeks of development. In the absence of SRY, an ovary results.

The fetal testicle begins producing hormones at the seventh or eighth week of pregnancy but direct development of the internal ducts and subsequently, external genitalia does not take place until week’s nine to 12.

In the presence of ovaries and in the absence of testicular hormones, the internal ducts and external genitalia follow a female path of development. While the ovary has been shown to produce hormones at the eighth week of pregnancy, the role of these hormones in sexual differentiation is unclear.

Phenotypic sexual differentiation: Before the eighth week of development, the internal reproductive ductal system is identical in the two sexes. As a result of testicular hormones, the rudimentary male ductal system develops and the female system disappears. At the tenth week of pregnancy, adjacent to the testicle, epididymis, vas deferens and seminal vesicle appear. In the female fetus in which testicular hormones are not produced, the rudimentary female internal ductal system develops and the male internal ductal system disappears. As a result, adjacent to the ovary, fallopian tubes, uterus and the upper vagina form. 

The fetal tissues that develop into male or female external genitalia are also bipotential.  Under the influence of testicular hormone (androgen), male external genitalia begin developing during the tenth week of pregnancy. In the third trimester, testicular hormone secretion results in growth of the penis and testicular descent. In the female fetus, in which no testicular hormone is circulating, the rudimentary tissues develop into a clitoris and labium.

What are ambiguous genitalia?

The medical term "intersex" is used to describe a number of conditions that affect the formation of the genitalia early in pregnancy, resulting in an appearance that is typical of neither a boy nor a girl. 

What causes ambiguous genitalia?

The reproductive organs and genitals associated arise from the same fetal tissue. If the genetic process that causes this fetal tissue to become "male" or "female" is disrupted, ambiguous genitalia can develop. Even if genetic sexual determination occurs uneventfully, hormonal sexual differentiation can be disrupted. For example, a baby could still have ambiguous genitalia due to inadequate or overabundant levels of the male sex hormone testosterone. The precise underlying cause can usually be determined so that a recommendation can be made as to the appropriate gender in which to raise the baby.

How is ambiguous genitalia classified?

Ambiguous genitalia ranges in degree of severity but the most common variations include:

True hermaphroditism: Children who have both male and female genitalia and internal reproductive organs.

Gonadal dysgenesis: Children who have internal organs that are primarily female, external genitals that may vary between normal female and normal male and an underdeveloped gonad.

Psuedohermaphroditism: Children who have questionable external genitalia but have only one gender's internal reproductive organs. For instance, a person may have a uterus, fallopian tubes and vagina but not a clearly defined clitoris and labia.

Congenital adrenal hyperplasia (CAH): Females with CAH are born with an enlarged clitoris and normal internal reproductive tract structures. Males have normal genitals at birth. CAH causes abnormal growth for both sexes; patients will be tall as children and short as adults. Females develop male characteristics and males experience premature sexual development.

How can the exact cause be identified?

The necessary investigations to determine the underlying cause of your baby's problem include various blood tests and an ultrasound of the abdomen and pelvic area. Investigation will also include a genitogram, which is a special X-ray test. During this test, a radiologist inserts a small catheter into the urethral opening and injects a contrast dye that will determine if a vagina exists. In addition, it may sometimes be necessary to take a sample of tissue from the gonads for examination under the microscope to be certain of their nature. 

What are some recommended treatments?

Surgery will also be offered so that the genitalia can look normal, like those of any other boy or girl. Nowadays, operations to correct masculinized female genitalia, when carried out by an experienced surgeon, are remarkably successful resulting in an appearance that is indistinguishable from that of a normal girl. Surgery, though, is not always necessary, particularly among girls with congenital adrenal hyperplasia (CAH) who are only slightly masculinized, as the clitoris often becomes less prominent as treatment to correct the underlying hormonal imbalance begins to take effect. A concealed vagina, however, will invariably need some surgery to bring its opening out onto the surface. When the vagina is hidden just under the skin, this is often carried out shortly after birth, although when it lies deeper in the pelvis, it is best delayed until one or two years of age. 

Surgeons are becoming increasingly aware that it is important for girls to retain normal sexual sensation after genital surgery. Therefore, in cases in which the clitoris is greatly enlarged, necessitating removal of a portion of the erectile bodies to improve appearance, great care is taken to avoid injury to the sensory nerves and to preserve the blood supply to the glans. It must be acknowledged, however, that there are few long-term follow-up studies to determine to what extent surgeons have been successful in achieving these objectives. It is, however, well recognized that, after vaginal surgery, there is a tendency for the newly created opening to narrow down. This sometimes necessitates further surgery, although more often, simple dilatations begun during the teenage years prior to any sexual activity are all that is required. 

Surgery for boys is usually successful in converting an ambiguous penis, which is usually tethered down with the urethral opening set well back towards the scrotum, into one that looks remarkably normal. Any separation of the scrotal sacs will usually be corrected at the same time. The operation is usually carried out between six months and 18 months of age and is frequently accomplished in one stage as an outpatient procedure. Once healed, the penis continues to grow in pace with the child's physical development, and further surgery is rarely needed. The structures necessary for sensation and erectile function are undisturbed by the surgery.

In boys who harbor a uterus, this is usually removed when the diagnostic laparoscopy or laparotomy is carried out. An associated vagina, if large, will usually be removed at the same time, although rudimentary structures can be left undisturbed in the knowledge that their presence is unlikely to cause any problem.

Frequently asked questions:

Will my child be able to produce children as an adult?

Babies with congenital adrenal hyperplasia (CAH) or pseudohermaphroditism can be regarded as potentially fertile once the underlying hormonal imbalance is corrected. Babies with other conditions must be evaluated on a case-by-case basis. For example, those with true hermaphroditism also have the potential to be fertile. Other girls, for example those with testicular dysgenesis, may have had their gonads removed because of the risk of tumor development, yet a well-developed uterus will have been left in place so it can potentially nurture an implanted embryo conceived in the laboratory using modern assisted reproductive techniques. Boys having at least one testicle, which on biopsy is shown to be normal, have the potential to be fertile, although this is by no means certain.

Will my baby have psychological problems down the road, particularly with regard to sexual preferences or gender identity?

Among girls whose external genitalia were only slightly masculinized at birth or who have undergone modern feminizing surgery, experts have no reason to think they will later be displeased by the appearance of their genitalia. Similarly, provided the caliber of the vagina is checked prior to the onset of sexual activity and adjusted, if necessary, such girls should be able to have intercourse without any problem.

Among boys, the correction of even severe hypospadias should not compromise their ability to have satisfactory intercourse. Ejaculation, however, may be rather less forceful than normal, particularly when it was necessary to reconstruct much of the penile urethra.

We are on rather less certain ground when it comes to the long-term psychosexual outcomes, particularly with regard to gender identity. In the past few years, we have become increasingly aware that testosterone, the hormone responsible for producing masculinization of the external genitalia, may potentially have had an effect on the developing brain, programming such an individual to think along male lines and, perhaps, even develop a male gender identity. This clearly has important implications when the decision is made to raise any masculinized infant as a girl. 

Further research is presently being undertaken to determine just how much weight should be given to such considerations when gender assignment of a baby with ambiguous genitalia is being considered. It is, though, very important to remember that human sexuality is a highly complex subject and that the long-term psychosexual functioning of any individual, even those born with perfectly normal appearing genitalia, can never be predicted with certainty.

Reviewed January 2011

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Normal and Abnormal Sexual Differentiation Glossary
  • abdomen: Also referred to as the belly. It is the part of the body that contains all of the internal structures between the chest and the pelvis.

  • adrenal: Glands that reside above the kidneys composed of an inner medulla and an outer cortex.

  • ambiguous genitalia: External genitalia which have physical characteristics falling somewhere between normal male and female, either of which may predominate.

  • androgen: Male sex hormone.

  • biopsy: A procedure in which a tiny piece of a body part (tissue sample), such as the kidney or bladder, is removed (with a needle or during surgery) for examination under a microscope; to determine if cancer or other abnormal cells are present.

  • CAH: Also known as congenital adrenal hyperplasia. A genetic disorder characterized by a deficiency in the hormones cortisol and aldosterone and an over-production of the hormone androgen, which is present at birth and affects sexual development.

  • catheter: A thin tube that is inserted through the urethra into the bladder to allow urine to drain or for performance of a procedure or test, such as insertion of a substance during a bladder X-ray.

  • cellular: Relating to small parts or groups.

  • chromosome: A structure consisting of DNA and proteins, found in the nucleus of a cell, which carries the genetic information in living organisms.

  • clitoris: Sensitive female sex organ, which is visible at the front of the vagina.

  • congenital: Present at birth.

  • congenital adrenal hyperplasia: Also known as CAH. A genetic disorder characterized by a deficiency in the hormones cortisol and aldosterone and an over-production of the hormone androgen, which is present at birth and affects sexual development.

  • dilatation: Process of widening or being widened.

  • embryo: A human offspring in the early stages following conception up to the end of the eighth week.

  • epididymis: A coiled tube attached to the back and upper side of the testicle that stores sperm and is connected to the vas deferens

  • erectile: Capable of filling with blood under pressure, swelling and becoming stiff.

  • external genitalia: The region of the body comprising of the penis and scrotum in males and the clitoris, vagina and labia in females.

  • fallopian tubes: There are two fallopian tubes, one on each side of the uterus. They transport an egg from the ovary to the uterus.

  • fertile: Able to produce offspring.

  • fetal: Relating to or characteristic of a fetus (unborn offspring after eight weeks of development).

  • fetus: An unborn offspring from the end of the eighth week of conception until birth.

  • gene: The basic unit capable of transmitting characteristics from one generation to the next.

  • genetic: Relating to the origin of something.

  • genitalia: External sexual organs.

  • genitals: Sex organs, including the penis and testicles in men and the vagina and vulva in women.

  • genitogram: X-ray examination of the internal genital duct system.

  • glans: The head of the penis.

  • gonad: The organ that forms the reproductive cells. In females, this is the ovary. In males, it is the testicles.

  • hormone: A natural chemical produced in one part of the body and released into the blood to trigger or regulate particular functions of the body. Antidiuretic hormone tells the kidneys to slow down urine production.

  • hyperplasia: Excessive growth of normal cells of an organ.

  • hypospadias: A birth defect in which the opening of the urethra, called the urinary meatus, is on the underside of the penis instead of at the tip.

  • internal genitalia: Internal reproductive organs.

  • intersex: An organism with characteristics of both sexes.

  • ions: Electrically charged atoms.

  • labium: Any of the four skin folds that surround the genital organs of a woman or girl.

  • laparoscopy: Surgery using an instrument in the shape of a tube that is inserted through the abdominal wall to give an examining doctor a view of the internal organs.

  • laparotomy: An operation in which the abdominal cavity is opened and inspected directly.

  • ovaries: Female reproductive organs that produce eggs and also produce the sex hormones estrogen and progesterone.

  • pelvic: Relating to, involving or located in or near the pelvis.

  • pelvis: The bowl-shaped bone that supports the spine and holds up the digestive, urinary and reproductive organs. The legs connect to the body at the pelvis.

  • penis: The male organ used for urination and sex.

  • pregnancy: The condition of being pregnant.

  • prostate: A walnut-shaped gland in men that surrounds the urethra at the neck of the bladder. The prostate supplies fluid that goes into semen.

  • pseudohermaphroditism: A congenital abnormality in which the external genitalia of a male or a female resemble those of the opposite sex.

  • radiologist: Doctor specializing in the interpretation of X-rays and other scanning techniques for the diagnosis of disorders.

  • renal: Pertaining to the kidneys.

  • scrotal: Relating to the scrotum, the sac of tissue that hangs below the penis and contains the testicles.

  • scrotal: Relating to the scrotum, the sac of tissue that hangs below the penis and contains the testicles.

  • scrotal sac: Also referred to as the scrotum. The sac of tissue that hangs below the penis and contains the testicles.

  • scrotum: Also referred to as the scrotal sac. The sac of tissue that hangs below the penis and contains the testicles.

  • secretion: Process of producing a substance from the cells and fluids within a gland or organ and discharging it.

  • seminal vesicle: Two pouch-like glands behind the bladder. They produce a sugar-rich fluid called fructose that provides sperm with a source of energy that helps sperm move. The fluid of the seminal vesicles makes up most of the volume of a man's ejaculatory fluid, or ejaculate.

  • stage: Classification of the progress of a disease.

  • testicle: Also known as testis. Either of the paired, egg-shaped glands contained in a pouch (scrotum) below the penis. They produce sperm and the male hormone testosterone.

  • testicular: Relating to the testicle (testis).

  • testicular dysgenesis: A condition in which the embryonic gonad fails to fully develop into a testis.

  • testosterone: Male hormone responsible for sexual desire and for regulating a number of body functions.

  • tissue: Group of cells in an organism that are similar in form and function.

  • true hermaphroditism: A classification of ambiguous genitalia where the gonads comprise well organized ovarian and testicular tissue. Sometimes this results in an ovary on one side and a testis on the other.

  • tumor: An abnormal mass of tissue or growth of cells.

  • ultrasound: Also referred to as a sonogram. A technique that bounces painless sound waves off organs to create an image of their structure to detect abnormalities.

  • urethra: A tube that carries urine from the bladder to the outside of the body. In males, the urethra serves as the channel through which semen is ejaculated and it extends from the bladder to the tip of the penis. In females, the urethra is much shorter than in males.

  • urethral: Relating to the urethra, the tube tha carries urine from the bladder to outside the body.

  • urge: Strong desire to urinate.

  • urology: Branch of medicine concerned with the urinary tract in males and females and with the genital tract and reproductive system of males.

  • uterus: A hallow, muscular organ in the pelvis cavity of females in which the embryo is nourished and develops before birth.

  • vagina: The tube in a woman's body that runs beside the urethra and connects the uterus (womb)to the outside of the body. Sometimes called the birth canal. Sexual intercourse, the outflow of blood during menstruation and the birth of a baby all take place through the vagina.

  • vas: Also referred to as vas deferens. The cordlike structure that carries sperm from the testicle to the urethra.

  • vas deferens: Also referred to as vas. The cordlike structure that carries sperm from the testicle to the ejaculatory duct, whicn in turn carries it to the urethra.

  • void: To urinate, empty the bladder.

  • Y chromosome: The sex chromosome that determines the male sex.

Normal and Abnormal Sexual Differentiation Anatomical Drawings

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