Paediatric Gynaecology and Differences in Sex Development

Introduction

Puberty should transform a girl into a fertile woman. Its social importance is so great that any deviation from normality may be the cause of considerable embarrassment and anxiety. This chapter describes normal puberty and outlines the management of both precocious and delayed puberty. It will also cover some of the gynaecological conditions which may affect pre- and post-pubertal girls.

Normal Puberty

Pathophysiology of normal puberty

The onset of pubertal development is heralded by an increase in pulsatile release of gonadotrophin-releasing hormone (GnRH) from the hypothalamus. Following brief activation of the GnRH neurons in the neonatal period, they remain in a dormant state until the onset of puberty. Initially, the pulsatile release of GnRH occurs only at night. However, as puberty progresses, it occurs throughout the day and night. Pulsatile GnRH release causes gonadotropic cells of the anterior pituitary to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These gonadotrophins lead to the production of ovarian estrogen, which initiates the physical changes of puberty.

Pubertal development

The external signs of puberty usually (but not always) occur in a specific order ( Fig. 3.1 ) and are described in five Tanner stages ( Figs. 3.2 and 3.3 ). Breast development (thelarche) is usually the first sign of puberty. Pubic and axillary hair (pubarche) normally develops about 6 months later, although in one-third of girls’ pubic hair may appear before breast development. Breast development occurs as a result of rising estradiol levels, and pubic and axillary hair by adrenal androgen secretion. Menarche occurs late in puberty, normally corresponding to the end of the growth spurt. Maximal growth velocity usually occurs after the start of breast and pubic and axillary hair development. However, in some girls, the growth spurt may be the first sign of puberty. The complete process of puberty is usually a slow progression, taking a minimum of 18 months.

Fig. 3.1, Schematic representation of puberty .

Fig. 3.2, Tanner stages of breast development .

Fig. 3.3, Tanner stages of pubic hair development .

During puberty, the ovaries enlarge and develop multifollicular cysts under the influence of pulsatile gonadotrophin secretion. The uterus also grows steadily through puberty. Due to the relative immaturity of the hypothalamic–pituitary–ovarian axis in the first 2 years following menarche, more than half of menstrual cycles are anovulatory, resulting in irregular cycles. After the first 1 to 2 years, the capacity for estrogen-positive feedback on the anterior pituitary develops with the subsequent mid-cycle LH surge and ovulation, resulting in regulation of the menstrual cycle. Anovulatory cycles are often heavy and prolonged, with some girls bleeding for several weeks at a time. This can lead to iron-deficiency anaemia and, in very rare cases, cardiovascular collapse requiring admission and blood transfusion. Initial anovulatory cycles tend to be pain free, although heavy menstrual loss can result in an element of dysmenorrhoea. When regular ovulatory cycles commence, the periods often become more painful due to the increased levels of circulating prostaglandins.

Age of menarche

Since the late 19th century, there has been a gradual decline in the age of menarche. In the United Kingdom, the average age of menarche has fallen from 15 years in 1860 to the current average age of 12.3 years. The onset of puberty will range between individuals, with 95% of girls showing signs of secondary sexual characteristics between the ages of 8.5 and 13 years.

Energy reserves and metabolic conditions play an important role in the timing of pubertal development. Leptin, a hormone released by adipose cells, is known to play a critical role in body weight homeostasis and the metabolic control of puberty. Childhood obesity is consistently associated with an early onset of puberty. Factors which delay the attainment of a critical body weight may delay puberty. These include malnutrition, eating disorders, and excessive exercise.

Variations of Normal Puberty

Premature adrenarche is the secretion of adrenal androgens resulting in the appearance of pubic hair before the age of 8 years. Axillary hair, body odour and acne may occur, but other secondary sexual characteristics do not. It can be slowly progressive or stay stable, and puberty usually begins at the normal time. Serum androgen concentrations may be slightly raised or normal. Gonadotrophin levels are pre-pubertal and bone age is normal.

Premature thelarche is defined as the premature development of breast tissue in the absence of other secondary sexual characteristics before the age of 8 years. The most common age of onset is within the first 2 years of life but can occur at any age. Progression to precocious puberty can occur in up to a third of girls.

Isolated premature menarche is the occurrence of vaginal bleeding in the absence of other secondary sexual characteristics. It is a diagnosis of exclusion after vaginal and uterine pathology, foreign body, and precocious puberty have been ruled out. It can be an isolated event or it can recur. Puberty will be expected to start at the normal time and final adult height will not be affected.

Precocious Puberty

The development of secondary sexual characteristics prior to the age of 8 years in girls constitutes precocious puberty and must be investigated. Central (gonadotrophin-dependent) precocious puberty occurs when there is a pituitary or hypothalamic cause. Peripheral (gonadotrophin-independent) precocious puberty occurs when puberty is induced by sex steroids from other causes, such as a hormone-secreting tumour. The growth spurt is a striking feature, but frequently it is the occurrence of menstruation which brings the girl to medical attention. In the event of vaginal bleeding, a local cause—such as a foreign body or malignancy—should always be ruled out. Children with precocious puberty should be under the care of a paediatric endocrinologist.

Causes of precocious puberty

Gonadotrophic-Dependent Precocious Puberty (GDPP)

In 90% of girls with GDPP, no cause is found. In the remaining 10%, causes are intracranial and include encephalitis, meningitis, cranial radiation, hydrocephaly, and space-occupying neoplasms, such as optic nerve gliomas. Sexual abuse has been reported as a precipitating cause.

Gonadotrophic-Independent Precocious Puberty (GIPP)

Causes of GIPP include feminising tumours of the ovary or adrenal, which may give rise to vaginal bleeding without signs of pubertal development. Other causes include hypothyroidism, and the very rare McCune–Albright syndrome, in which cystic cavities develop in the long bones (polyostotic fibrous dysplasia) and café-au-lait skin pigmentation is evident. Estrogen-secreting cysts are found in the ovaries on ultrasound. Other rare causes include ingestion of exogenous estrogens.

Investigation of precocious puberty

1
Plasma FSH, LH, estradiol, and thyroid function tests
2
X-ray of the hand to determine bone age, which may be advanced
3
Ultrasound scan of the abdomen and pelvis
4
Radiological skeletal survey of the long bones if McCune–Albright syndrome is suspected
5
Cranial magnetic resonance imaging (MRI) scan.

In the constitutional and cerebral forms, the ovaries may show a multicystic appearance on ultrasound as seen in normal puberty. Ultrasound will also distinguish between a follicular cyst, which will be expected to subside spontaneously, and a predominantly solid estrogen-secreting granulosa/theca cell tumour of the ovary, which will require surgical removal.

Care of children with precocious puberty

With precocious puberty the aims of treatment are to:

1
Suppress menstruation and prevent progression of puberty
2
Maximise growth potential and
3
Achieve psychological well-being.

Not all children need treatment, as symptoms may only be slowly progressive. Treatment prevents progression but does not usually reverse changes that have already happened. If an underlying aetiology is found, this should be treated.

GnRH agonists suppress gonadotrophin secretion. Depot injections are given every 3 months and treatment can be continued for 2 to 3 years without significant side effects. Treatment is stopped when an acceptable age for puberty is reached.

Delayed Puberty

Delayed puberty in girls is defined as the absence of physical manifestations of puberty by the age of 13 years. Primary amenorrhoea is the absence of menarche and needs to be evaluated in the context of secondary sexual characteristics. The diagnosis may be made by age 15 years if a patient has normal secondary sexual characteristics or if menarche has failed to occur by 2 years post breast budding. In some instances, a girl may enter puberty but the normal progression is not maintained. This is described as ‘arrested puberty’.

Causes of delayed puberty

These features of delayed puberty fall into three main categories ( Table 3.1 ).

Table 3.1

Differential Features of Delayed Puberty

	Stature	Gonadotrophins	Gonadal steroids	Karyotype
Constitutional delay	Short	Pre-pubertal	Low	Normal
Hypogonadotrophic hypogonadism	Normal	Low	Low	Normal
Primary gonadal failure:
Turner syndrome and variants	Short	High	Low	XO and variants
Gonadal dysgenesis	Normal/tall	High	Low	XX or XY

Constitutional delay

Constitutional delay is the most common cause of delayed puberty. These girls are normal but just inherently late at entering puberty. They are usually of short stature, but their height is generally appropriate for their bone age. All stages of development are delayed. They may be considered to be physiologically immature, with a functional deficiency of GnRH for their chronological age but not for their stage of physiological development. There is frequently a history of delayed menarche in their mothers.

In these patients, bone age shows a better correlation with the onset and progression of puberty than does chronological age. On attaining a bone age of 11 to 13 years, they can be expected to enter puberty.

Hypogonadotrophic Hypogonadism

This is caused by the deficient production, secretion, or action of GnRH. It may be associated with:

Conditions affecting body weight, such as chronic systemic disease, malnutrition or anorexia nervosa.
Central nervous system tumours—the most common of these rare conditions is craniopharyngioma. Girls may also have associated growth hormone deficiency and, therefore, short stature.
Isolated gonadotrophin deficiency. Such patients are generally of appropriate height for chronological age. The association of hypogonadotrophic hypogonadism with anosmia or hyposmia is called Kallmann syndrome, which results from incomplete embryonic migration of GnRH-synthesising neurons. This occurs in 50% of cases.

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