INTERSEX

The first question a mother asks after her baby has been born is ‘Is it a boy or a girl?’ The answer is given after looking at the infant’s genitals, but in two neonates out of 10 000 the genital sex is ambiguous and the child is judged as being intersex.

Most neonates with ambiguous genitals are genetically female and have congenital adrenal hyperplasia. A few have an adrenal tumour or drug-induced virilism. In rare cases the neonate is a hermaphrodite, having a testis, an ovary and ambiguous external genitals.

Congenital adrenal hyperplasia (CAH)

This condition affects one in 10 000 neonates and is due to a group of enzyme defects which prevent the synthesis of cortisone from progesterone. The lack of circulating cortisone permits the hypothalamus–pituitary to release quantities of corticotrophins, which stimulate the adrenal gland to secrete androgens, with resulting virilization of the external genitals (Fig. 41.1).

Fig. 41.1 Ambiguous external genitalia due to the adrenogenital syndrome.

The most common enzyme defect is C21-hydroxylase deficiency (found in more than 90% of cases). In three-quarters of cases ambiguous external genitals are the only sign of the condition, but in a quarter of cases aldosterone production is lost and the patient has a salt-losing syndrome.

Any child with ambiguous genitals should be investigated for CAH, by determining the chromosomal sex and by measuring the 17-hydroxyprogesterone level (a level of more than 7 mmol/L confirming the diagnosis) and checking the serum electrolytes. Treatment should be effected urgently or death may supervene from salt loss. The infant is treated with cortisone or one of its derivatives and careful follow-up is essential, but surgical correction of the external genitals should be delayed for 3–4 years.

Other causes of intersex

Other varieties of intersexuality are not diagnosed until after puberty, when menstruation fails to start. They include gonadal dysgenesis (Turner’s syndrome), testicular feminization (androgen insensitivity syndrome) and Klinefelter’s syndrome (seminiferous tubular dysgenesis).

Gonadal dysgenesis

There are two varieties of this condition, pure gonadal dysgenesis and Turner’s syndrome.

Pure gonadal dysgenesis

In this disorder, genital hypoplasia is detected in a girl who has normal breast development. A chromosomal analysis shows a mosaic 46, XO/XX.

Gonadal dysgenesis/Turner’s syndrome

Turner’s syndrome is caused by the deletion of some or all of the genes on the X chromosome. The classic Turner’s syndrome karyotype is 45, X, but the majority have a mosaic pattern with a normal second cell line (e.g. 45, X/46, XX or 45, X/46, XY). The incidence is between 1/2000 and 1/5000 in liveborn infants (99% do not survive to term).

In adolescence the classic features are short stature and arrested or delayed puberty (Fig. 41.2). Only 9% with the 45, X karyotype have a complete spontaneous puberty compared with 40% of those with mosaicism. Spontaneous pregnancy is rare (2%); more likely in the mosaic form, but has been reported in the 45, X variant. The standard management is to administer growth hormone and some women can achieve normal adult height. As most have arrested pubertal development, hormone replacement therapy is carefully introduced to complete feminization over 2–3 years. These women need careful supportive counselling, especially to deal with the sexuality and infertility issues.

Fig. 41.2 Gonadal dysgenesis (Turner’s syndrome). The patient is of short stature and has a ‘webbed’ neck. Pelvic examination showed a vagina and a rudimentary uterus, but palpable gonads.

Testicular feminization

Physically, the person is female with female external characteristics, including good breast development (Fig. 41.3) and has been reared as a girl. She and her parents are concerned when she fails to menstruate. Examination shows that she has a short vagina, which ends blindly. Her karyotype is 46, XY, as she is genetically male. The gonads are in the abdominal cavity or in a hernial sac. They synthesize testosterone, but the body tissues lack α-reductase enzyme to convert it to di-hydroxytestosterone, and receptor cells in genital tract tissues and skin may be missing. As the testes may become malignant they should be removed and hormonal replacement treatment given.

Fig. 41.3 Incomplete testicular feminization.

THE ‘GENITAL CRISIS’

In a few female infants, because of tissue sensitivity, maternal oestrogen thickens the vaginal and uterine epithelium. After birth, the oestrogen is withdrawn and the child has a small withdrawal bleed per vaginam, the so-called ‘genital crisis’. Similarly, a few female infants may secrete a small amount of watery milk. The parents require assurance.

FUSION OF THE LABIA MINORA

The labia may be seen to be adherent at the neonatal examination, or this may occur when the girl is a toddler. The treatment is to separate the labia with the fingers and for the mother to apply an oestrogen cream to the separated labia for 2–3 weeks to encourage epithelialization.

VULVOVAGINITIS IN PREPUBERTAL CHILDREN

Vulvovaginitis may occur at any age. The child is brought by the mother complaining of an inflamed, tender vulva and, perhaps, a vaginal discharge. The causes are listed in Table 41.1. The vulval area should be inspected and an anal swab taken for pin and thread worms. A swab should be taken from the vagina. If an intravaginal foreign body is suspected and cannot easily be detected the child should be referred to a gynaecologist who deals with children, for examination with a vaginoscope.

Table 41.1 Vulvovaginitis: causes

Percentage
1. Non-specific		60
2. Specific
a. Bacterial E. coli N. gonorrhoeae Other		20
b. Fungal (Candida)		10
c. Protozoal (trichomonad)		5
d. Foreign body		5
e. Helminthic/viral		1

Treatment consists of:

If the condition persists for more than 2 weeks in spite of these treatments, oestrogen cream may be applied to the vulva and vaginal introitus twice daily for 5 days.

PRECOCIOUS PUBERTY

Precocious puberty indicates that sexual maturation has occurred before the age of 9. Most cases are constitutional in origin, but ovarian or adrenal hormone-secreting tumours must be excluded. The investigations include:

Management is psychological and endocrine. The girl (and her parents) needs considerable psychological support as she perceives herself as different from her peers and may be teased. If the girl’s bone age is advanced she will be taller initially but, as the epiphyses fuse earlier, she will ultimately be shorter than her peers. There is a paucity of high quality evidence about the benefits, particularly long term, of hormonal or drug treatment for precocious puberty.

PHYSICAL CHANGES OF PUBERTY AND EARLY ADOLESCENCE

The endocrinological changes that occur before and after puberty are detailed in Chapter 2. These changes manifest in physical changes (Table 41.2). If they do not parallel, fairly closely, the changes in their peers, some girls become anxious and seek reassurance. Others may develop an eating disorder.

Table 41.2 Time of appearance of sexual characteristics in girls

By the age of 17 over 99% of adolescents will have reached menarche. Delay after this age may be constitutional or have a recent cause (Table 41.3). Investigations include:

Table 41.3 Primary amenorrhoea

The history and examination may indicate special examinations, for example measurement of FSH; imaging of the skull or the pelvic organs; nuclear sex chromatin; laparoscopy. Treatment is discussed in Chapter 28.

MENSTRUAL DISTURBANCES IN ADOLESCENCE

Menstrual disturbances are discussed in Chapter 28. As mentioned, in the first 2 years after the menarche some young women experience oligomenorrhoea, whereas in others menstruation occurs at longer or shorter intervals. Unless the disorder persists, treatment consists of reassuring the young woman that it will settle.

Later in the teenage years dysfunctional uterine bleeding affects a small number of young women. Many of the invasive investigations listed for older women are inappropriate for teenagers. For example, hysteroscopy is invasive and usually not necessary. Treatment using hormones is the main modality, as endometrial ablation and hysterectomy are inappropriate. Hormonal treatment or treatment with NSAIDs, e.g. mefenamic acid, for 3–6 months usually controls the menstrual disturbance, after which reciprocity of the hypothalamopituitary–ovarian axis re-establishes itself, but in 5% of affected adolescents the dysfunctional uterine bleedings recur. If the menstrual disturbance does not resolve quickly with the suggested treatment, a screen for coagulation abnormalities is indicated.

Dysmenorrhoea affects many adolescent women and is considered on page 232.