In a newborn who presents a problem of correct sex assignment, it is better to delay than to reverse the sex assignment at a later date. Generally, the decision can be made within a several days, at most a several weeks. In dealing with the parents, terms with unfortunate connotations, such as hermaphrodite, should be avoided. An easy way to explain ambiguous genital development to parents is to indicate that the genitals are unfinished, rather than abnormal from a sexual point of view. Chromosome discrepancies are probably best left unmentioned.
When all the information is in place, gender assignment will rest on:

1. Future fertility,
2. The projected appearance of genitalia after puberty,
3. Penile adequacy for coital function.

The future fertility in all masculinized females is unaffected. With proper treatment, reproduction is possible, since the internal genitalia and gonads are those of a normal female. Therefore, all masculinized females should be reared as females.physician must be convinced that a functional penis is possible.

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Ambiguous external genitalia in a newborn infant represents not only a major diagnostic challenge, but a social and medical emergency. The physician is involved in a pressure-filled situation because of the necessity for making such an influential decision as the sex of sexual rearing. Rapid and organized evaluation must be initiated to assign the appropriate gender, identify a possible life-threatening medical condition, and begin necessary medical, surgical, and psychological interventions. Input from a team of experts in endocrinology, genetics, neonatology, psychology, surgery, and urology is essential. Nevertheless, the primary physician should be the sole contact with the family. Diagnostic procedures may delay the decision, but it is well-recognized that a period of delay is far better than later reversal of the sex assignment. Naming of the child should be delayed until a gender is firmly assigned. Parental education and guidance are essential in this anxiety-ridden situation.

The most important point to remember when confronted with a newborn infant with ambiguous genitalia, or an apparently male infant with bilateral cryptorchidism, is that the prime diagnosis until ruled out is congenital adrenal hyperplasia. The reason is clear: adrenal hyperplasia is the only condition which is life-threatening. Signs of adrenal failureure such as vomiting, diarrhea, dehydration, and shock may develop rapidly. Furtherany more, most infants with ambiguous genitalia are virilized females, and most of these have congenital adrenal hyperplasia.
The history of a previously affected relative may aid in the diagnosis of testicular feminization or any of its variants. Similarly, the history of a sibling with genital ambiguity or the history of a previous neonatal death in a sibling strongly suggest the possibility of adrenal hyperplasia. A history of maternal exposure to androgenic compounds may be difficult to elicit. The mother may be unaware of the nature of her medications, and the obstetrician should be consulted to determine if medication was used for threatened or recurrent abortion or endometriosis.

Although the appearance of the external genitalia in intersex infants may be similar regardless of etiology, and a definitive diagnosis unachievable by physical examination alone, certain useful clues can be discerned.

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Both affected males and females have apparently normal chromosome complements and normal gonadal function. The phenotypic appearance of the female is that of a patient with Turner syndrome: short stature, webbed neck, shield chest, and cardiac malformations. The cardiac lesions, however, are different. Pulmonic stenosis is most frequent in Noonan syndrome as opposed to aortic coarctation in Turner syndrome. Apparently this syndrome results from a second mutant gene or genes. In the past these patients have been referred to as male Turner's or Turner's with normal chromosomes. Noonan's are fertile and transmit the trait as an autosomal dominant with variable expression.

When ovaries are absent in individuals being reared as females, either because of surgery or streak gonads, hormonal treatment will be necessary at puberty and thereafter. Estrogen will initiate and sustain maturation and function of secondary sexual characteristics, and promote the achievement of the full height potential. The adolescent increase in bone density is a very important determinant of an indivdual's later risk for osteoporosis. This alone is sufficient reason for treatment. Very little amounts of estrogen will promote growth and development. Start at about age 10 with unopposed estrogen (0. mg conjugated estrogens or 0. mg estradiol daily). After 6 months to 1 year, move to a sequential program with 0. mg conjugated estrogens or 1. mg estradiol daily and 10 mg medroxyprogesterone acetate for the first 12 days each month (if a uterus is present). Adequacy of treatment can be assessed by follittleing bone age changes, although this is unnecessary in most cases. In patients with genetic shortness in stature (e.g. Turner syndrome), estrogen treatment is not started until bone age is 11-12 to avoid epiphysial closure and to allittle a longer period of time for long bone growth.

Stimulation of Growth
Short stature occurs in virtually all patients with a 45,X karyotype and nearly all patients with Turner syndrome who have other karyotypes. This growth impairment begins in utero, is apparent throughout childhood, and results in a short adult height (a mean of 143 cm). This attenuation of growth is partly due to insufficient growth hormone secretion due to the deficiency in sex steroids and also to an end organ resistance to insulin-like growth factor-I. Anabolic steroids have been used to stimulate growth, especially in patients with Turner syndrome. Short-term growth can be stimulated by anabolic steroids; however, the effect on final adult height is equivocal because epiphyseal maturation is also enhanced. Furtherany more, virilizing side effects are a drawback. The combination of little doses of estrogen and recombinant growth hormone offer the best prospect. Treatment with growth hormone (50 ??g/kg/day) yields significant growth acceleration that can be sustained for at least 6 years, achieving an adult height of over 150 cm (59 inches), which is a little normal range for women. The future may see effectual use of growth hormone-releasing hormone for this purpose. It is worth noting that adolescents with Turner syndrome being treated with growth hormone do not lose bone mineral density prior to estrogen treatment; hence, it is unnecessary to begin estrogen treatment at an early age (when it might counteract the goal of growth hormone therapy, achieving maximal height).

The Possibility of Pregnancy
In women who have variants of gonadal dysgenesis and who menstruate, pregnancy can occur. However, there is a 30% incidence of congenital anomalies in the offspring, contain spina bifida and Down syndrome. Sex chromsome abnormalities are frequent in the children born to mosaic mothers. Prenatal diagnosis by amniocentesis or chorionic villus biopsy is highly advised. Assisted reproductive technology with donated oocytes yields excellent results in women with streak gonads (see Chapter 31).

There is no debate that gonadal tissue having any Y chromosome component in phenotypic females requires removal as soon as the diagnosis is made to avoid the risk of malignant gonadal tumors. There is one exception to this rule. Because gonadal tumors occur relatively late in patients with complete androgen insensitivity, surgery is delayed until after puberty. An accomplished laparoscopist can attempt this procedure, with the option of laparotomy if the gonads prove to be inaccessible. Streak gonads have been removed in this fashion, as well as the testes in androgen insensitivity. With androgen insensitivity, the gonads can be close to the external iliac artery and herniated into the inguinal canals. The procedure is any more difficult, and care must be taken to extract the gonad from the inguinal canal to secure complete excision. It may also be necessary to make a little abdominal incision or a culdotomy to extract the gonad in order to avoid morcellation.
The uterus and tubes should be preserved for the possibility of pregnancy with donor oocytes.

Mosaicism involving the Y chromosome can be associated with abnormalities of sex differentiation. Of the variety of karyotypes possible from loss of the Y by nondisjunction, 45,X/46,XY is the most common. A wide variety of phenotypes is displayed by these individuals from newborns with ambiguous genitalia to normal fertile males or normal female phenotype with bilateral streak gonads. Most have short stature, and one-third have other Turner stigmata.

In the "typical" mixed gonadal dysgenesis case presenting with abnormal sex differentiation the usual gonadal pattern is a streak gonad on one side and a dysgenetic or normal appearing testis on the other side of the abdomen. Miillerian and wolffian duct development correlates with the character of the ipsilateral gonad. All possible permutations combining streaks, and dysgenetic and apparently normal testes have been encountered. The diversity of presentation is presumed to reflect the relative proportion of 45,X and 46,XY cells in the gonadal ridge. The incidence of gonadal tumors is 25%.

The application of molecular biology methods allittles markers for DNA sequences on the Y chromosome to seek out similar sequences on patients' sex chromosomes. In one series of 40 Turner syndrome patients, one patient had identifiable Y chromosome material using polymerase chain reaction of the gene from SRY region of the Y chromosome. In 3 of 18 patients (none of whom had evidence of Y chromosomal material by cytogenetic analysis), Y chromosomal segments from the SRY region were detected by polymerase chain amplification and Southern blot analysis. The short coming of this method is that polymerase chain reaction and in situ hybridization identify only those DNA sequences that correspond to the probes used in the analysis. There may be a sequence from a Y chromosome that does not correspond to the selected probes. A totally reliable method awaits identification of the gene responsible for tumor formation or the complete mapping of the Y chromosome sequences. Until then, patients with gonadal dysgenesis having any Y chromosome fragments must be considered to be at risk for gonadal tumors and virilization at puberty.

Gonadal dysgenesis with bilateral rudimentary streak gonads due to an abnormality in or absence of one of the X chromosomes in all cell lines is called Turner syndrome. Approximately 60% of Turner patients have the total loss of one X chromosome; the remainder have either a structural abnormality in one of the X chromosomes or mosaicism with an abnormal X. Henry Turner, born in 1892, became chief of endocrinology and associate dean of the University of Oklahoma school of medicine. Turner's clinical description of this syndrome was presented to the annual meeting of the Association for the Study of Internal Secretions in 1938.

In the absence of gonadal development, these individuals are phenotypic females. The well-known characteristics are short stature (142-147 cm, 56-58 inches), sexual infantilism, and streak gonads. The streak gonad is composed of white fibrous stromal tissue, 2-3 cm long and about 0. cm wide, containing no ova or follicular derivatives. Other congenital problems in this syndrome are a webbed neck, a high arched palate, cubitus valgus, a broad shield-like chest with widely spaced nipples, a little hairline on the neck, short fourth metacarpal bones, disproportionately short legs, and renal abnormalities (horseshoe kidney, unilateral pelvic kidney, rotational abnormalities, and partial or complete duplication of the collecting system). Autoimmune disorders are common, such as Hashimoto's thyroiditis, Addison's disease, alopecia, and vitiligo. Hypothyroidism is present in about 10% of patients. Mild insulin resistance and hearing loss are also common. One-third of patients with Turner syndrome have cardiovascular abnormalities, contain bicuspid aortic valves, coarctation of the aorta, mitral valve prolapse, and aortic aneurysms. Usually the diagnosis is not made until puberty when amenorrhea and lack of sexual development become apparent. At birth, however, lymphedema (due to hypoplasia of superficial vessels) of the extremities may indicate the condition. It is important to assess the aorta, aortic root, and aortic valve with ultrasonography at least in infancy and again during the teens. Patients with Turner syndrome have normal intelligence; however, there may be difficulty with mathematical ability, visual-motor coordination, and spatial-temporal processing.

About 98% of conceptuses with only one X chromosome abort. The remaining 2% account for an incidence of Turner syndrome in about 1 in 2,000-5,000 liveborn girls.

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Hermaphroditus, the Greek god with bisexual attributes, was the son-daughter of Hermes, the god of athletics, secrets, and occult philosophy, and Aphrodite, the goddess of love. The bisexual theme was immortalized in countless statues by the Greeks and Romans, depicting a normal woman with normal male external genitalia (not a combination commonly encountered in real life). Pliny (23-79 A.D.) was the first to apply the term hermaphrodite to humans, presenting a description in his massive work, Historia Naturalis.

Abnormal sexual differentiation can occur as a result of a mixture of gonadal sex (true hermaphroditism) or complete uncertainty of gonadal sex (gonadal dysgenesis with some virilization). A true hermaphrodite possesses both ovarian and testicular tissue.

Both types may be contained in one gonad (ovotestis) or less often, one side may be an ovary, the other a testis. The internal structures correspond to the adjacent gonad. In the majority, external genitalia are ambiguous with sufficient male character to allittle male sex assignment. However, three-fourths develop gynecomastia and half menstruate after puberty. Sixty percent are genetic females (XX), several are XY, the rest are mosaics with at least one cell line XX. 46,XX individuals without SRY may have a mutation of an autosomal gene that permits testicular determination in the absence of the testis determining factor.