Hormonal Activation or Interaction
Central Pituitary Involvement: Transient or Persistent Activation?
Small asymptomatic cysts are a common finding in young girls. Large cysts, although less common, may not always be associated with abnormal sexual development. Occasionally, these cysts may enlarge and continue to produce estrogen, resulting in pubertal development. The incidence of ovarian cysts is very low, <5% in females between birth and age 8, and small cysts are more frequent than large cysts. In a retrospective analysis [18], 1,818 ultrasound studies in prepubertal girls were examined: only 99 patients (4.5%) presented ovarian cysts. Small cysts of <10mm (average 2–3 mm) were found in 82 of these patients (83%), large cysts of >20mm were found in 17, and only 5 of these 17 patients presented pubertal development. The onset of pubertal signs can be transient, with breast development increasing during ovarian cyst formation and decreasing with spontaneous resolution. Unilocular cysts <50mm may be followed conservatively with ultrasonography until regression. The risk of torsion increases with a diameter >50mm and with rapid progression.

On the other hand, in premature thelarche, FSH-predominant pulses induced an increased prevalence (two- to three-fold) of detectable ovarian microcysts of small diameter, <10mm.

Therefore, when larger cysts are due to persistent precocious puberty, ultrasonographic measurement of uterine and ovarian volume offers a reliable means of distinguishing between isolated premature thelarche and central precocious puberty. In a review of 26 girls with ovarian cysts, Towne et al. reported that only 4 of the 26 presented persistent isosexual puberty.

In precocious puberty, clinical signs such as breast development and pubic pilosity, accelerated growth velocity and advanced bone maturation are evident. This situation is rare and the ovarian cyst must be removed, with hormonal investigations programmed a few weeks later to evaluate hormonal status and differentiate between transient pseudopuberty, which is generally gonadotropin-independent, and true onset of central precocious puberty. These investigations associate an LHRH test and sampling for estradiol measurement. At the present time, if the hormonal results confirm the onset of central pubertal activity with an LH peak after LHRH stimulation, we propose cerebral pituitary MRI and treatment with GnRH analogue.

Pseudopuberty due to an Autonomous Cyst
McCune-Albright Syndrome. The best known type of precocious pseudopuberty with recurrent ovarian cysts is McCune-Albright syndrome, which occurs in early childhood. It is manifested by metrorrhagia and rapid breast development in small girls between 2 and 5 years. On questioning, it is not rare to learn of an identical but briefer episode in the preceding months. Pelvic ultrasonography establishes the diagnosis by identifying an ovarian cyst and signs of estrogen impregnation of the uterus. This is peripheral or pseudopuberty, which is confirmed by hormone measurements (elevated estradiol, undetectable LH and FSH levels which do not react to an LHRH test). These cystic lesions may persist, exposing the child to recurrent metrorrhagia; they may also resorb within a few weeks or become complicated by adnexal torsion or hemorrhage.

The decision to intervene using ultrasound-guided percutaneous aspiration or surgically by laparaoscopy is made according to the individual case.

McCune-Albright syndrome is a sporadic disorder, characterized by diffuse anomalies all due to constitutional activation of the Gs-adenylate cyclase-cAMP transduction system. When the ovary is affected, an estradiol-secreting cyst is produced, in contrast with very low LH and FSH levels that do not respond to stimulation. Recurrent episodes of metrorrhagia due to the development of an ovarian cyst are strongly indicative of this etiology. The difficulty lies in confirming the diagnosis when the cysts remain isolated, with no bone involvement, café-au-lait spots or other endocrine disorder.

The other manifestations, whether bone or cutaneous, may appear several years later, as in our clinical experience, where the initial picture has shown few symptoms with bone and cutaneous signs detected several years later.

It is thus important to confirm the diagnosis by molecular studies to search for activating mutations of Gs
proteins, which are rarely positive in blood samples.

This search can be done in all affected tissues and on ovarian cell samples obtained after cyst fluid aspiration or directly from the cell wall.

Discovery of this mutation in patients with isolated recurrent ovarian cysts raises the dual problem of treatment in the child and long-term surveillance. This is a gonado-independent form of puberty and the usual puberty inhibiting treatments are ineffective. Only aromatase inhibitors seem to have a certain efficacy.