R. Stanhope, C. Traggiai
Department of Endocrinology, Great Ormond Street Hospital for Children and
The Middlesex Hospital (UCLH), London, UK
Two decades ago, the diagnosis of premature sexual development was considered to be simple; the conditions that were recognised were either central precocious puberty, isolated premature thelarche or an adrenal aetiology. The use of pelvic ultrasound and gonadotrophin-releasing hormone (GnRH) analogue treatment was to completely alter our understanding of these disorders.
Pelvic ultrasound led to differentiating ovarian appearances in conditions such as McCune-Albright syndrome and the variation in ovarian maturation in premature thelarche and central precocious puberty. Failure to respond to GnRH analogue therapy in children with precocious puberty led to the concept of gonadotrophin-independent precocious puberty (GIPP).
During the 1980s, several variants of premature sexual maturation were described and this was important, both for the natural history of these conditions and the requirement for therapy. Adrenal lesions causing sexual maturation are included in this chapter for completeness. Their diagnosis and management is considerably simpler than premature sexual maturation of a gonadal aetiology.
In the diagnosis of disorders of premature sexual maturation, there are two investigative procedures of significance, which are simple and relatively easy to interpret: the GnRH test and pelvic ultrasound assessment.
Pelvic ultrasound is a non-invasive technique which gives two important pieces of information. The uterine volume (and the endometrial thickness) is a measure of oestrogen secretion. The ovarian morphology can be used as an index of gonadotrophin secretion. The initial hormonal events of normal puberty are predominantly LH, rather than FSH, dependent.
There is a nocturnal rise in LH pulsatility and the amplitude gradually increases. When the corresponding increase in oestrogen becomes sufficient to induce breast development, then phenotypic puberty has commenced. However, the endocrine events that culminated in the onset of phenotypic puberty have been occurring for several years. Ovarian morphology changes from about 8 years of age and, in response to pulsatile nocturnal gonadotrophin pulsatility, the ovary develops into a multicystic morphology. The multicystic morphology contains more than six follicles of 4mm in diameter, or greater.
This morphology is different from a polycystic ovarian appearance. The multicystic ovarian appearance is a marker for the presence of pulsatile nocturnal gonadotrophin secretion. Thus, this ovarian morphological appearance is always present in girls with central precocious puberty, as it is in girls with normal puberty. Other disorders of premature sexual maturation have other characteristic morphological appearances, but not multicystic, and these are described in the sections below. With a progressive increase in amplitude of gonadotrophin pulsatility, the next stage of ovarian development, after multicystic, is the appearance of a dominant follicle, >10mm in diameter.
The GnRH stimulation test has relatively little use in delayed puberty but is of enormous significance in investigating children with premature sexual maturation. Girls with central precocious puberty have a dominant LH response to a bolus of intravenous GnRH, whereas girls with premature thelarche have a predominant FSH response. There is a broad spectrum between these two extremes and this will be discussed under the various specific diseases below.
Certainly, without a dominant LH response, it is almost certain that there will be no response to GnRH analogue therapy. Of course, children without a gonadotrophin response to a bolus injection of GnRH are likely to have GIPP, which will require an alternative treatment regimen.
In the investigation of adrenal disorders, an ACTH stimulation test is often helpful and, by measuring intermediate steroid metabolites, such as serum 17-hydroxyprogesterone, as well as urinary steroid metabolites of both cortisol and androgen metabolism, it is possible to distinguish the specific lesion in adrenal steroid biosynthesis.
Revision date: June 14, 2011
Last revised: by Janet A. Staessen, MD, PhD