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International journal of endocrinology 6 (70) 2015

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Girls Precocious Sexual Development: Capability of Laboratory Diagnosis

Authors: Lutsenko L.A. - Kyiv Municipal Clinical Center of Endocrinology, Kyiv, Ukraine

Categories: Endocrinology

Sections: Specialist manual

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Summary

Важность своевременного выявления причин преждевременного полового развития обусловлена прежде всего возможным наличием опухолевого процесса, а также теми состояниями, которые сопровождают ускоренный пубертат. Ключевую роль в диагностике и контроле эффективности лечения преждевременного полового развития играют лабораторные методы исследования.

Важливість своєчасного виявлення причин передчасного статевого розвитку обумовлена насамперед можливою наявністю пухлинного процесу, а також станами, що супрово-джують пришвидшений пубертат. Ключову роль у діагностиці та контролі ефективності лікування передчасного статевого розвитку відіграють лабораторні методи обстеження.

The importance of timely detection of the causes of precocious sexual development is associated, firstly, with the possible existence of tumor, as well as with the states accompanied by the accelerated puberty. Key role in the diagnosis and the monitoring of effectiveness of precocious sexual development treatment belongs to the methods of laboratory examination.


Keywords

преждевременное половое развитие, 17-ОН-прогестерон, кортизол, лютеинизирующий гормон, фолликулостимулирующий гормон, антимюллеров гормон.

передчасний статевий розвиток, кортизол, лютеїнізуючий гормон, фолікулостимулюючий гормон, антимюллерів гормон.

precocious sexual development, cortisol, luteinizing hormone, follicle stimulating hormone, anti-Muller’s hormone.

Sexual development is a genetic process of the transformation of child’s organism into grown-up’s one that is capable of reproduction. The terms of the beginning of puberty are affected by the following factors: non-modified (genetic) and modified (endocrinologic diseases, overweight, level of physical activity, social conditions, exogenous admission of hormones). Modified factors may potentially be corrected.

The period of sexual development is important stage of child’s development. The activation of endocrine mechanisms of regulation of girls’ sexual development begins in the age of 6-7 but the initial element of puberty remains vague. Continuous process of sexual development is divided as usual into discrete stages proposed as a criterion for visual assessment in 1969–1970 by W. Marshall and J. Tanner; later the methodology was approved by WHO.

Thelarche is the first sign of girls’ sexual development. It occurs at average in the age of 10.5. Pubarche appears in few months after the beginning of enlargement of breasts. It is the first sign in 15 % of girls. Menarche begins as a rule in 2 years after the beginning of enlargement of breasts.

Precocious sexual development (PSD) is the appearance of secondary sexual characters in girls in the age of 8. The prevalence of PSD depends on: nosological unit, sex and age. Recently this disease is becoming more and more prevalent. The urgency of this issue is caused by the development of such complications of PSD (in case of absence of treatment) as short stature (the result of preterm closure of growth plates of cortical bones), dysplastic physique (short limbs, long body, wide pelvis), premature sexuality, obsession, dysfunction of reproductive system (pubertal uterine hemorrhage, dysfunctional uterine hemorrhage in reproductive age, polycystic ovarian syndrome, premature menopause). Therefore, the necessity of diagnosis and treatment of PSD is universally recognized.

The diagnosis of PSD should be made in 2 stages.

First stage – validation of PSD. Clinical diagnosis is based on the assessment of sexual development stage according to the Tanner scale. Anthropometry and calculation of the rate of child’s growth during preceding 6-12 months are obligate. X-ray study of hands with wrist joints is necessary one allowing detecting bone age. If bone age outgrows real age more than 2 years, than PSD is confirmed.

Second stage – differential diagnosis of nosological entities of PSD in order to choose treatment tactics. This stage includes instrumental and laboratory methods of study. In case of diagnostic search the results of clinical examination should be taken into account in the first place.

The progress of girls’ PSD according to heterosexual type (abnormal constitution of external sex organs, the beginning of pilosis) requires the abnormalities caused by the hypersecretion of androgens (congenital adrenal cortical hyperplasia (CACH), androgen-producing tumors of gonads or adrenal glands) to be excluded. The emphasis during the examination should be made on laboratory diagnosis. The determination of 17-OHP, cortisol, dehydroepiandrosterone sulfate (DHEAS), androstendione and testosterone is obligate. If high concentration of 17-OHP and/or DHEAS and testosterone in blood is detected, low-dose dexamethasone suppression test should be made. In case of normal range the concentration of 17-OHP, DHEAS and testosterone reduces by 50% or more; the absence of time course of the hormone concentration may show that there is androgen-producing tumor. Suspected case of androgen-producing tumor requires further instrumental diagnosis - ultrasonography/MRT of pelvic organs and adrenal glands.

If high concentration of 17-OHP, DHEAS and low or normal concentration of cortisol are detected it is necessary to exclude nonclassical form of CACH. Probe with synthetic adrenocorticotropic hormone of short or durable effect (tetracosactide) should be made. If the level of 17-OHP is 20-30% higher than its basal level (in case of girls with premature pubarche) it may be nonclassical form of CACH. According to the recommendations of International Society of Endocrinology the detection of 17-OHP level should be made early in the morning during follicular phase: standard basal 17-OHP is 2-4 ng/ml, stimulated 17-ОНР is <10 ng/ml.

Molecular-genetic methods of study are applied to confirm monogenic form of PSD.

Therapeutic tactics is determined by the etiological PSD. PSD treatment is aimed at the regress of secondary sexual characters, the stopping of menstruation, improvement of growth prognosis through slowing down the accelerated rates of skeleton ossification.

If hormone-active adrenal glands/gonads tumor is detected, surgical methods of treatment should be applied. Moreover, surgical treatment should be applied if there is a need in correcting girls’ external sexual organs in the setting ofCACH.

The treatment of heterosexual PSD in the setting of CACH consists of substitutive hormonotherapy with the help of glucocorticoids. The control over treatment should be exercised according to the level of 17-OHP (target level is upper normal level). Testosterone and blood renin should also be taken under control.

Clinical girls’ PSD according to the isosexual type is similar to the changes during sexual development: enlargement of breasts with subsequent pilosis, body feminization.

Luteinizing hormone (LH) is the most informative in the diagnosis of gonadotropin-dependent PSD. The employment of high-strung methodology and the presence of pre-puberty norms in the laboratory are a must during laboratory examination. Less diagnostic value has follicle-stimulating hormone (FSH). The usage of gonadotrophic index (LH/FSH) helps to differentiate fast-growing forms of PSD (the ratio is indicated above) from slowly-developing ones that do not require treatment. Estradiol allows confirming the PSD diagnosis when there is evident progression of PSD, and it is not informative at early stages.

Additional index allowing confirmation of PSD is anti-Mullerian hormone. The level of this hormone is hardly if not possibly detected before girls’ sexual development. In the setting of puberty the growth of the index may be observed.

For the purpose of differential diagnosis of gonadotropin-dependent forms of PSD the stimulating probe of gonadotropin-independent and of isolated thelarche with gonadotropin-releasing hormone should be made.

The next step in the diagnostic search is the employment of instrumental methods. Ultrasonography of pelvic organs allows not only detecting PSD signs but it is also an additional method of differential diagnosis between vera PSD and isolated thelarche.

Instrumental diagnosis in case of PSD may also include MRT pelvic organs and MRT of brain. MRT of brain is made when gonadotropin-dependent character of PSD is proved.

Nowadays the analogs of gonadotropin-releasing hormone are used for the treatment of vera PSD. The precondition of the therapy with the help of durable analogs of gonadotropin-releasing hormone is the continuity of the therapy, calendaring and shot compliance.

The assessment of the therapy effectiveness should be made no earlier than 3 months after the beginning of the treatment, then every 6 months based on the total of clinical and laboratory indexes. 


Bibliography

1. Карева М.А. Федеральные клинические рекомендации — протоколы по ведению пациентов с врожденной дисфункцией коры надпочечников в детском возрасте / М.А. Карева, И.С. Чугунов // Проблемы эндокринологии. — 2014. — Т. 60, № 2. — С. 42-50.

2. Speiser P.W. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline / P.W. Speiser, R. Azziz, L.S. Baskin et al. // J. Clin. Endocrinol. Metab. — 2010. — Vol. 95(9). — Р. 4133-4160.

3. Johansen M.L. Anti-Müllerian Hormone and Its Clinical Use in Pediatrics with Special Emphasis on Disorders of Sex Development / M.L. Johansen, C.P. Hagen, T.H. Johannsen et al. // International Journal of Endocrinology. — 2013. — Vol. 10.

4. Касаткина Э.П. Диферелин: перспективы использования в практике детского эндокринолога / Э.П. Касаткина, Л.Н. Самсонова, Е.В. Киселева // Фарматека. — 2003. — № 16. — С. 10-12.

5. Карева М.А. Федеральные клинические рекомендации по ведению пациентов с преждевременным половым развитием / М.А. Кареева // Проблемы эндокринологии. — 2013. — № 6. — С. 50-56.

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