Precocious Puberty
Dr. Mrs. Meena P. Desai
Consultant Pediatrician
Sir Hurkisondas Nurrotumdas Hospital,
Hon. Director, Sir H.N. Medical Research Society,
Consultant-Endocrinology Division
Bai Jerbai Wadia Hospital For Children, and
Institute of Child Health & Research Centre.

First Created: 02/25/2001 

Introduction

When would you consider pubertal development as precocious?

There are variations in the onset of puberty in various parts of the word. It is generally considered precocious when any of the sex characteristics appear before the age of 8 years in girls and 9 years in boys. Menarche before the age of 10 years is also precocious.

What are the various forms of precocious sexual development? How do you classify?

Puberty can occur prematurely due to early activation of the hypothalamic-pituitary-gonadal(HPG) axis or due to underlying pathologic conditions involving the gonads, adrenals, or ectopic sites. When the HPG axis is activated it is known as central or gonadotropin dependent true precocious puberty (CPP or TPP). Peripheral or pseudo precocious puberty (PPP) is gonadotropin independent. Here the pubertal development is partial or incomplete. CPP may be idiopathic or due to various CNS lesions. It is isosexual with complete physical and sexual maturation and establishment of reproductive gonadal function. Individual differences exist in their rate of progression. PPP can be iso or heterosexual, with only some of the sexual characteristics appearing early.

Occasionally CPP supervenes over PPP when the advanced state of skeletal maturation and the elevated sex steroid levels due to adrenal (e.g. CAH) or gonadal (ovarian cyst.) pathology provoke early maturation of the hypothalamic-pituitary axis.

Besides these, there are conditions referred to as variants of pubertal development, which include premature thelarche (PT), and premature adrenarche (PA) or rarely premature menarche. These are more commonly encountered in girls and occur as isolated unsustained non-progressive phenomena. Linear growth and skeletal maturation are not usually advanced. This group of children requires careful periodic observation as these isolated phenomena may occasionally herald the onset of CPP/TPP. Complete workup and intervention may become necessary in the event of further progression.

Central Precocious Puberty (CPP) or True Precocious Puberty (TPP)

What causes CPP/TPP?

CPP occurs as an extreme variation of normal due to early HPG axis activation which may be idiopathic or it may be related to neurogenic causes with a spectrum of CNS lesions. In these instances, there is a premature decrease in the sensitivity of the gonadostat. In true precocity, the sexual maturation, growth spurt, and advanced bone age are associated with pubertal levels of estrogens or androgens variable rise in the levels of gonadotropins. Increased rate of ossification results in the early closure of epiphyses.

Are there any specific sex differences as regards CPP?

True or central precocious puberty is more common in females and the idiopathic form accounts for over 80% of cases in females but only 40% males. Organic causes involving the CNS are important in boys. Overall it is 10 fold more common in girls than boys.

Which is the commonest CNS lesion causing CPP?

In our country, TBM or other inflammatory lesions of CNS are important. With the availability CT and MRI, underlying lesions like hypothalamic hamartomas are detected in patients who would have been diagnosed as idiopathic CPP in the past. Hamartoma is a nonprogressive hypothalamic development malformation, which constitutes an ectopic site for the production of gonadotropin-releasing hormone (GnRH) that influences gonadotropin secretion. This abnormality may be associated with seizure disorders, especially gelastic epilepsy, and occasionally with variable degrees of mental subnormality.

Are there any other causes of precocious sexual development?

One of the most intriguing complexes is the unusual syndrome of sexual precocity associated with juvenile hypothyroidism. This is the only form of sexual precocity where growth is arrested rather than stimulated. McCune Albright Syndrome may also be associated with CPP but frequently PPP due to ovarian cysts. A syndrome of gonadotropin independent precocious puberty resembling the true from has now been identified as occurring more frequently in males (familial testotoxicosis) and probably accounts for some of the familial forms of CPP reported in the past. The inheritance is sex-limited autosomal dominant. Tumors like hepatoblastoma or teratoma may also produce CPP by releasing GnRH. Drugs or accidental ingestion of hormone-containing pills, inadvertent use of anabolic steroids, food or vitamins contaminated with artificial estrogens, foreign body, or tumors of the genital tract are some of the other causes which may cause confusion.

Is clinical evaluation helpful in diagnosis?

Careful history taking and detailed physical examination are important. Early age of onset and rapid progression may favor hypothalamic hamartoma; delayed milestones may signify congenital abnormalities or perinatal brain damage while regression may suggest postnatal intracranial infections or trauma. Symptoms and signs of increased intracranial pressure favor the possibility of a space-occupying lesion. Family history of early puberty in mother or close female relatives favor familial predisposition.

Physical examination should assess pubertal staging which is important in management and follow up, physical measurements, growth velocity (if the previous height is available) and growth status as well as careful general, systemic, and CNS examination are extremely important in arriving at a diagnosis.

It is important to distinguish TPP from other forms of incomplete or pseudosexual precocity of peripheral origin as the underlying cause and management differ. More than one sign of sexual maturation with accelerated growth velocity, physical growth, and advanced bone age is indicative of the center from TPP. Early TPP is often indistinguishable from premature thelarche and often a policy of wait and watch and follow up evaluation has to be adopted. Occasionally isolated breast development may persist for six months or more hence diagnostic difficulties arise in distinguishing early CPP from premature thelarche.

In boys examination of the gonads is very helpful; bilateral enlargement favors CPP while as lack of it in the presence of other signs of sexual precocity is seen with adrenal causes such as CAH. Asymmetrical enlargement of testis indicates testicular pathology such as a functioning testicular tumor, which is rare.

What investigations are helpful?

Bone age is advanced in TPP and is extremely helpful at the time of initial diagnosis as well as on follow up. Pelvic sonography for uterine and ovarian size and morphology is necessary and also help in excluding a primary ovarian pathology. Bilateral enlargement of ovaries with small follicular cysts and enlargement of the uterus favors HPG axis activation. CNS imaging is very valuable in excluding intracranial organic lesions and detecting hypothalamic hamartomas. Vaginal cytology shows a marked estrogen effect in TPP. The hormonal evaluation includes the estimation of sex steroids, serum estradiol (>10pg/ml), or testosterone (>0.2ng/ml) and gonadotropins (>1 IU/L) which may be in the pubertal range. LH, FSH response to GnRH stimulation test with an LH/FSH ratio exceeding 1, favors CPP.

Study of thyroid hormones, adrenal androgens, and 17 - hydroxyprogesterone may be undertaken as indicated. ACTH stimulation and dexamethasone suppression tests may be required in girls with premature adrenarche to differentiate from a primary adrenal disease such as congenital adrenal hyperplasia. Adrenal imaging is occasionally required to exclude virilizing adrenal tumor. Bilateral adrenal hyperplasia may be seen in cases with CAH.

What are the goals of management in these children?

The management is directed towards reversing and preventing further progression of puberty, the arrest of skeletal maturation which compromises height potential and dealing with the emotional and psychological problems which are frequently encountered. These children should be guarded against sexual abuse.

GNRH Agonist

What are the indications for the use of GnRH agonists? How it should be given?

The use of drugs in the idiopathic form of TPP is influenced by the age of onset of symptoms and the rapidity of progression. When CPP is rapidly progressive and occurs in a young child with the possibility of compromising height potential, the best form of medical therapy available today is with GnRH agonist. Chronic administration of these compounds down-regulates and desensitizes GnRH receptors on pituitary gonadotropes. This leads to inhibition of gonadotropin release followed by decreased secretion of sex steroids. Depending on the nature of the preparation, GnRH can be administered by the SC route or intranasally daily or in a long-acting repository form every 4 weeks. Within 2-4 weeks of adequate treatment with these agonists, the mean LH response to GnRH is within the prepubertal range and the sex steroid levels are suppressed by 4-12 weeks. The secondary sex characters regress and the accelerated growth velocity and bone age advance are slowed during the first year of therapy.

Leuprolide Acetate (Lupron depot ped) is the only depot preparation approved in the USA and is given as 0.25 to 0.3 mg/kg, a minimum of 7.5 mg IM once in 4 weeks. Triptorelin available here as (Decapeptyl) is used in doses of 60 to 75 mcg/kg IM once in 3 to 4 weeks. Aqueous daily S.C. injection of leuprolide 50 mcg/kg twice a day or intranasal nafarelin (Synarel) 800 mcg bid are other preparations.

Therapy should be monitored in these children at regular intervals, with gonadotropin and sex steroid levels maintained in prepubertal range in both the sexes. Skeletal maturation is retarded to a greater degree than linear growth with a resultant increase in prediction for adult stature. An occasional allergic reaction may occur otherwise no toxic reactions are reported. Medical therapy is advisable for nonprogressive neurogenic lesions causing CPP including postmeningitic forms or hamartomas.

What treatment modalities are available?

Treatment varies with the underlying cause.GnRH agonists, Medroxyprogesterone Acetate (MPA), and Cyproterone Acetate (CPA) are used for gonadotropin dependent CPP.

GnRH independent sexual precocity in the females (e.g. ovarian cysts) is usually treated with MPA, or occasionally with testolactone. In boys, CAH is the usual cause of peripheral sexual precocity and is treated with corticosteroids. Testotoxicosis is a rare condition treated with ketoconazole, spironolactone, and flutamide.

The normal variation of pubertal development such as premature thelarche, premature isolated menarche, and premature adrenarche are benign and self-limited conditions requiring careful follow up without the institution of therapy. Surgery, radiation, or chemotherapy are required for CNS tumors. Occasionally pedunculated hamartomas have been extirpated.

The unusual syndrome of sexual precocity associated with juvenile hypothyroidism is reversible with the institution of thyroid therapy.

In peripheral incomplete forms of sexual precocity, GnRH-A is ineffective. Testolactone a competitive inhibitor of the enzyme aromatase which converts androgens to estrogens has been used in gonadotropin- independent McCune Albright Syndrome. MPA has been useful in the treatment of recurrent ovarian cysts, McCune Albright Syndrome, and familial testotoxicosis. If TPP supervenes before/after treatment of PPP, GnRH-(A) therapy may be added.

How effective are other forms of treatment in CPP?

Medroxy progesterone acetate (MPA) has been administered I.M. in doses varying from 50 to 400 mg per month (initially 100 mg/m2) or daily orally as 5 mg twice to four times a day. It is available freely, is more economical, and is effective in controlling menses and secondary sex characters. Cyproterone acetate(CA) has been used in doses varying from 100 to 150 mg/m2/day in 2-3 divided doses. Both MPA and CA can suppress gonadotropin secretion in addition CA has an antiandrogenic effect. Both these drugs have very little effect on linear growth or skeletal maturation, which continues to progress.

Can normal pubertal development resume when GnRH treatment is discontinued? Any other problems related to treatment?

Within 6 to 18 months of discontinuation of treatment, normal pubertal development is resumed. Long term use may decrease the bone mass density as skeletal calcification may be affected to some extent. Occasionally polycystic Ovarian Syndrome (PCOS) is described.


Precocious Puberty Precocious Puberty 02/25/2001
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