Pediatrics

Endocrine Causes of Vaginal Bleeding in the Prepubertal Girl

OVERVIEW: What every practitioner needs to know

Are you sure your patient has an endocrine cause for vaginal bleeding? What are the typical findings for this disease?

Vaginal bleeding is rare in prepubertal girls but may occur in a number of endocrine disease states. These include congenital conditions such as McCune-Albright syndrome and acquired abnormalities such as central precocious puberty or severe primary hypothyroidism. The associated signs and symptoms vary tremendously and will depend on the specific cause. Awareness of the differential diagnosis and a careful, systematic evaluation are essential to confirm the endometrial source of the bleeding and to reveal the underlying cause.

Endocrine causes of vaginal bleeding in prepubertal girls typically result in the sudden onset of painless vaginal bleeding that may be profuse. Depending on the underlying cause, additional signs of secondary sexual development such as breast enlargement may be present. The history and physical examination will provide important clues as to the cause of the bleeding and serve to guide the diagnostic work-up.

The clinical features present in any given case will reflect the pathophysiology of the process responsible for the vaginal bleeding and will exist within a heterogeneous spectrum. For example, vaginal bleeding in a girl with central precocious puberty is accompanied by a history of gradual and progressive pubertal development, linear growth acceleration, evidence of both estrogen and androgens, and accelerated skeletal maturation. In stark contrast, girls with vaginal bleeding in the setting of primary hypothyroidism have linear growth failure and symptoms such as decreased energy, cold intolerance, and constipation. Each of these entities is discussed in more detail below.

What other disease/condition shares some of these symptoms?

The differential diagnosis of endocrine causes of vaginal bleeding in a prepubertal girl includes the following:

McCune-Albright syndrome

Profound primary hypothyroidism

Juvenile granulosa cell tumor

Central precocious puberty

Isolated functional ovarian cyst

Premature menarche

Each of these conditions will be discussed below.

What caused this disease to develop at this time?

McCune-Albright syndrome (MAS): Vaginal bleeding in girls with MAS arises from the development of large, unilateral, autonomously functioning ovarian cysts. The disease is extremely rare and is caused by an activating mutation in the stimulatory subunit of the heterotrimeric G-protein complex known as Gs alpha. The mutation occurs in a postzygotic cell line and exists in a mosaic configuration.

Classic MAS consists of the triad of precocious puberty, fibrous dysplasia of bone, and café au lait macules. Episodes of precocious puberty are intermittent and unpredictable. During an active episode, estradiol levels are extremely high and gonadotropins are suppressed. Resolution of the cysts results in withdrawal bleeding, which is how most girls with MAS come to medical attention. On physican examination, subtle breast development is usually present. Many girls also have typical café au lait macules.

Profound primary hypothyroidism: Rarely, children with long-standing severe primary hypothyroidism experience a form of pseudoprecocious puberty, also called Van Wyk–Grumbach syndrome. In girls, this takes the form of breast development and, occassionally, vaginal bleeding. Thus, girls may present to a gynecologist or to an emergency department before the diagnosis of hypothyroidism is uncovered.

The pathophysiology of this phenomenon is believed to be cross-reactivity of thyroid-stimulating hormone (TSH) at the level of the follicle-stimulating hormone (FSH) receptor, which in turn stimulates estradiol production by ovarian granulosa cells. Paradoxically, skeletal maturation is extremely delayed and linear growth arrest occurs. Luteinizing hormone (LH) levels will be prepubertal, and pelvic ultrasonography will reveal polycystic ovaries. Classic signs and symptoms of hypothyroidism will also be present.

Juvenile granulosa cell tumor: Up to 70% of girls with juvenile granulosa cell tumors have precocious puberty. This typically takes the form of gradual secondary sexual development with or without vaginal bleeding. Abdominal pain and/or distention along with a palpable mass are common features. Tumor markers are positive and imaging reveals a solid or cystic mass usually larger than 5 cm.

Central precocious puberty (CPP): CPP refers to early activation of the hypothalamic-pituitary-gonadal axis and has the same physiologic characteristics as normally timed puberty. Vaginal bleeding in this setting represents menarche and would occur only after several years of pubertal development, linear growth acceleration, and advancing skeletal maturation. Therefore, one would hope that a child would come to medical attention for concerns of precocious puberty before reaching this physical milestone.

Isolated functional ovarian cyst: Occasionally young girls will experience an isolated episode of vaginal bleeding with or without a documented ovarian cyst on pelvic ultrasonography. The precise cause is unclear but may be related to a transient flare in hypothalamic-pituitary-ovarian axis activity or an atypical form of MAS.

Premature menarche: Although still included in textbooks, the actual existence of this obscure entity is highly suspect. The term classically refers to menstrual bleeding without any other signs of pubertal development. In this author's experience, girls who present with a chief complaint of vaginal bleeding who are prepubertal on physical examination and have normal growth and skeletal maturation do not have an endocrinologic cause for their bleeding.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

LH, FSH and estradiol determinations are the most helpful tests. During an acute episode of vaginal bleeding due to MAS, gonadotropin levels will be suppressed and estradiol levels will be extremely elevated. If a high index of suspicion exists, additional screening for other manifestations of MAS would also be indicated.

TSH and free T4 would be the most important. Measuring antithyroid antibodies would be helpful in confirming the likely cause. In pseudoprecocious puberty, the TSH level is typically much greater than 100 and may be as high as 2000, and thyroxine levels are extremely low.

Depending on the findings of the physical examination, measuring both estrogen and androgen levels would be indicated, as well as gonadotropin concentrations. Tumor markers would also be helpful and results are typically positive with the diagnosis of granulosa cell tumor.

The gold standard for the diagnosis of CPP is a gonadotropin-releasing hormone (GnRH) analog stimulation test, with a positive result usually defined as a stimulated LH value greater than 6. A random ultrasensitive LH determination, when clearly elevated, which is defined as greater than 0.3 mIU/L, may also be used to confirm the diagnosis. FSH levels are less specific but depending on the assay used, may be as high as about 4 mIU/L in a prepubertal girl.

No specific laboratory values are pathognomonic for isolated ovarian cyst. LH, FSH, estradiol, TSH, and free T4 determinations should be considered. Suppressed gonadotropins would be consistent with this diagnosis, and estradiol levels may be normal or elevated.

If the physical examination is completely normal, the option of doing no laboratory studies should be entertained. An ultrasensitive LH determination can provide additional objective evidence that the hypothalamic-pituitary-ovarian axis is prepubertal. Ultrasensitive refers to the most sensitive methodology, which typically uses an immunochemiluminometric assay. The advent of ultrasensitive assays has allowed for discrimination between pubertal and prepubertal LH levels in a random (i.e., unstimulated) sample, which was not possible using older generation assays.

Would imaging studies be helpful? If so, which ones?

All children presenting with abnormalities of growth or puberty should have a radiograph of the left hand and wrist to determine bone age. In the setting of precocious puberty, it may be normal or advanced depending on the duration and extent of sex steroid exposure. In the case of severe hypothyroidism, skeletal maturation is profoundly delayed. In girls suspected of having MAS, an ovarian tumor, an ovarian cyst, or premature menarche, pelvic ultrasonography is the most helpful study. Uterine and ovarian dimensions as well as the presence or absence of an ovarian cyst or mass and endometrial stripe will aid in the evaluation. In girls with confirmed CPP, magnetic resonance imaging of the head is typically performed to rule out a structural abnormality of the hypothalamus or pituitary gland.

Confirming the diagnosis

Please see the recommended laboratory studies outlined above.

If you are able to confirm that the patient has this disorder, what treatment should be initiated?

The initial management of precocious puberty in the setting of MAS is observation, as most girls have only infrequent episodes of vaginal bleeding. In girls with frequent episodes, treatment options consist of antiestrogenic agents in the form of estrogen receptor blockers or an aromatase inhibitor. Although none has proved perfect, the most promising agents studied thus far are tamoxifen, letrozole, and Faslodex.

The treatment for hypothyroidism is levothyroxine replacement therapy. When hypothyroidism has been long standing, it is recommended that treatment be initiated with a very low dose that is gradually increased until euthyroidism is achieved. The addition of growth-promoting therapies such as growth hormone, GnRH analogs (GnRHa), and aromatase inhibitors are considered experimental.

The primary treatment of an ovarian tumor is surgical and will not be discussed here.

The gold standard for the treatment of CPP is a GnRHa. The long-acting preparations are the most widely used and include monthly and 3-monthly leuprolide and the subcutaneous histrelin implant. Studies using a 6-monthly GnRHa preparation also appear promising.

By definition, a functional ovarian cyst would be expected to be a transient phenomenon not requiring treatment.

As mentioned above, premature menarche is a descriptive and poorly defined entity without a clear underlying pathogenesis and no standard therapy.

What are the adverse effects associated with each treatment option?

Tamoxifen has been associated with increases in uterine and ovarian volumes, the significance of which is unclear. Letrozole has been associated with ovarian torsion in at least one case. No serious adverse effects have been reported with the use of Faslodex thus far. Pseudotumor cerebri has rarely been reported with levothyroxine treatment. There are the standard risks associated with surgery when removing an ovarian tumor. Rarely, sterile abscesses have been reported in patients receiving intramuscular injections of leuprolide. Mild insertion site reactions are common in children treated with the histrelin implant, and breakage of the implant during explantation is also fairly common.

What are the possible outcomes of this disorder?

Families need to understand the risk of additional endocrinopathies and the need for ongoing surveillance. They also need to know that episodes of precocious puberty are unpredictable. If they occur often enough, progressive pubertal development and advanced skeletal maturation with impairment in height potential would be expected to occur.

Once rendered euthyroid, the signs and symptoms of hypothyroidism will abate. However, some children end up with a permanent height deficit.

Tumor recurrence would be the biggest issue in terms of prognosis and needs to be discussed with the treating oncologist.

Long-term outcomes of children treated for CPP are excellent. However, the gain in height is significant only in girls treated when younger than 6 years of age.

There are no known long-term outcomes of isolated ovarian cysts or premature menarche.

What will you tell the family about the risks/benefits of the available treatment options?

Antiestrogenic agents in MAS can halt vaginal bleeding episodes and attenuate pubertal progression, linear growth acceleration, and advancing skeletal maturation. However, we have very limited information on the long-term follow-up of girls receiving these medications and there may be unforeseen risks associated with their use.

There is only one treatment option for hypothyroidism and it is completely safe. Withholding therapy would not be an option.

The only treatment option for a juvenile granulosa cell tumor is surgery.

Some options for the treatment of CPP involve more discomfort than others and require more compliance. All preparations of GnRHa are expensive.

What causes this disease and how frequent is it?

Epidemiology

MAS is extremely rare. The cause of the genetic mutation is unknown.

Hypothyroidism is common in the general population and particularly in girls and women. The most frequent cause is Hashimoto thyroiditis, which is an autoimmune condition.

Juvenile granulosa cell tumors account for a very small percentage of childhood tumors. The cause is unknown.

CPP is 10-23 times more common in girls than in boys and is usually idiopathic in girls. In boys, approximately 50% of cases are caused by a central nervous system (CNS) abnormality.

Isolated functional ovarian cyst is an uncommon occurrence and is believed to be due to a transient "flare" in hypothalamic-pituitary-ovarian activation.

The cause of premature menarche is unknown.

Genetics

MAS: This condition is caused by a postzygotic gain of function mutation in Gs alpha, the stimulatory subunit of the G-protein complex.

Profound primary hypothyroidism: A propensity for autoimmune disease is seen in many families and is likely due to complex interactions between multiple genes, only some of which have been identified.

Juvenile granulosa cell tumor: No specific genetic risk factors have been identified.

CPP: Genetic etiologies for CPP are increasingly being recognized and may be heritable or occur in a sporadic fashion. Thus far, mutations in the kisspeptin (KISS1) gene, KISS1 receptor, and makorin ring finger 3 (MKRN3) gene have been implicated in cases of CPP. A family history of CPP is present in up to 20% of affected children.

Isolated functional ovarian cyst: Nothing is known about the genetics of this condition.

Premature menarche: Nothing is known about the genetics of this condition.

How do these pathogens/genes/exposures cause the disease?

MAS: There is unregulated and autonomous G-protein–mediated signal transduction in endocrine cells.

Profound primary hypothyroidism: Dysregulation of the immune system results in an inflammatory process within the thyroid gland that ultimately interferes with its function.

Juvenile granulosa cell tumor: Unknown

CPP: Both single-gene mutations in KISS1 and its receptor result in prolonged signaling of the Kisspeptin/GPR54 pathway from a mutant protein resistant to degradation. Mutations in MKRN3 are expressed only from the paternal allele as this gene is maternally imprinted. Loss of function of this gene leads to a loss of inhibition normally exerted on the HPG axis by the MKRN3 protein.

Isolated functional ovarian cyst: Unknown

Premature menarche: Unknown

Other clinical manifestations that might help with diagnosis and management

MAS: The café au lait macules in MAS have a characteristic irregular "coast of Maine" configuration. Fibrous dysplasia of bone can cause facial asymmetry or bony deformities, which are often subtle. Some children with MAS have a mildly enlarged thyroid gland.

Profound primary hypothyroidism: Additional clinical signs of hypothyroidism include a puffy sallow appearance, extremely dry skin and hair, coarse facial features, delayed relaxation phase of reflexes, bradycardia, and a narrow pulse pressure.

Juvenile granulosa cell tumor: Abdominal distention and a palpable mass

CPP: Headaches in the setting of a CNS abnormality

Isolated functional ovarian cyst: None

Premature menarche: None

Are additional laboratory studies available; even some that are not widely available?

In MAS, molecular genetic analysis of the Gs alpha gene could be undertaken but would have the highest yield if affected tissue, rather than peripheral blood, was available.

Genetic studies could potentially reveal the etiology of CPP but are not commercially available at this time.

How can this disorder be prevented?

There is no known prevention of the diseases discussed.

What is the evidence?

Feuillan, PP. "McCune-Albright syndrome". Curr Ther Endocrinol Metab. vol. 6. 1997. pp. 235-9.

(This is a basic description of the pathogenesis and clinical characteristics of MAS.)

Lumbroso, S, Paris, F, Sultan, C. "Activating Gs alpha mutation: analysis of 113 patients with signs of McCune-Albright syndrome—a European Collaborative Study". J Clin Endocrinol Metab. vol. 85. 2004. pp. 2107-13.

(This provides helpful information regarding the likelihood of identifying the Gs alpha mutation in patients suspected of having the disease.)

Collins, MT, Singer, FR, Eugster, E. "McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia". Orphanet J R Dis. vol. 7. 2012. pp. 7-14.

(A description of the manifestations of MAS beyond fibrous dysplasia.)

Haddad, N, Eugster, E. "An update on the treatment of precocious puberty in McCune-Albright syndrome and testotoxicosis". J Pediatr Endocrinol Metab. vol. 20. 2007. pp. 653-61.

(A review of treatment options for precocious puberty in girls with MAS.)

Browne, LP, Boswell, HB, Crotty, EJ. "Van Wyk and Grumbach syndrome revisited: imaging and clinical findings in pre- and postpubertal girls". Pediatr Radiol. vol. 38. 2008. pp. 538-42.

(This paper describes the clinical and radiographic features of pseudoprecocious puberty in the setting of severe hypothyroidism.)

Cabrera, SM, DiMeglio, LA,, Eugster, EA. "Incidence and characteristics of pseudoprecocious puberty because of severe primary hypothyroidism". J Pediatr. vol. 162. 2013. pp. 637-639.

(An investigation of the incidence and clinical features of pseudoprecocious puberty among children with profound primary hypothyroidism.)

Schultz, KA, Sencer, SF, Messinger, Y. "Pediatric ovarian tumors: a review of 67 cases". Pediatr Blood Cancer. vol. 44. 2005. pp. 167-73.

(Discussion of juvenile granulosa cell tumors in the context of ovarian tumors of childhood.)

Nabhan, ZM, West, KW, Eugster, EA. "Oophorectomy in McCune-Albright syndrome: a case of mistaken identity". J Pediatr Surg. vol. 42. 2007. pp. 1578-83.

(This describes features that should help differentiate between juvenile granulosa cell tumor and MAS in girls presenting with sudden onset vaginal bleeding.)

Carel, JC, Eugster, EA, Rogol, A. "Consensus statement on the use of gonadotropin-releasing hormone analogs in children". Pediatrics. vol. 123. 2009. pp. e752-62.

(This is a consensus statement on the use of GnRHa in children, including indications for treatment, diagnosis, monitoring, and long-term outcomes.)

Fuqua, JS. "Treatment and outcomes of precocious puberty: an update". J Clin Endocrinol Metab. vol. 98. 2013. pp. 2198-207.

(A review of etiologies and treatment options for precocious puberty.)

Bulcao Macedo, D, Nahime, BV, Latronico, AC. "New causes of central precocious puberty: the role of genetic factors". Neuroendocrinology. vol. 100. 2014. pp. 1-8.

(A description of genetic etiologies of CPP and their pathophysiology.)

Ongoing controversies regarding etiology, diagnosis, treatment

MAS: The optimal therapy has not yet been identified and ongoing investigation continues.

Profound primary hypothyroidism: Whether a prolonged time course to euthyroidism or the addition of growth-promoting therapies will improve prognosis for adult height is unknown.

Juvenile granulosa cell tumor: Some of the presenting features overlap with MAS and it is known that some girls with MAS undergo unnecessary oophorectomy because of this. A pediatric endocrinologist should always be consulted for vaginal bleeding in a prepubertal girl.

CPP: Although it is often used to justify treatment, the psychological consequences of either treated or untreated CPP have not been well delineated.

Isolated functional ovarian cyst: There are no controversies regarding this condition.

Premature menarche: The biggest controversy revolves around whether this is a real phenomenon.

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