P recocious puberty can occur
due to exogenous hormone administration in the form of oral hormone
pills, estrogen containing creams, cosmetics, as well as estrogen
contaminated food. We report an unusual estrogen exposure leading to
precocious pseudopuberty in two siblings and gynecomastia in their
father.
Case Report
A seven year old female child was brought by her
mother with a history of two episodes of vaginal bleeding and
bilateral breast development. She had menstruated twice, each time
lasting for 3 days, with moderate flow and the interval between the
two cycles was 22 days.
There was no history of recent growth spurt,
headache, visual disturbances or café-au-lait spots on the skin. On
examination, her height was 92.5 cm and weight 21 kg. She had sparse
axillary and pubic hair. Breasts were of Tanner stage III. Nipples
and areolae were hyperpigmented. External genitalia were of
prepubertal type and there was no nipple discharge. Ocular fundus
examination was normal.
A detailed family history was elicited. Her
mother attained menarche at the age of 14 years. The girl had one
younger brother of 5 years age. He was found to be having
gynecomastia with no other abnormality. At request, the father also
consented for examination and was found to be having bilateral
gynecomastia without any galactorrhea. The father was employed in a
pharmaceutical company where oral contraceptives were manufactured.
In that company, his job was to supervise the site where tablets
were made from the hormone powder. After returning from his duties,
he used to play with the children for 2-3 hours daily and then only
he used to change from the office clothes. This was his routine for
about previous 2 years.
Investigations of the girl child revealed uterine
size of 5.4×4.0×2.1cm with endometrial thickening of 6 mm on
ultrasound. Right ovary measured 1.3× 1.5 cm and left ovary measured
1.3×1.4 cm without any follicles. Adrenals were not enlarged.
Magnetic resonance imaging scan of the brain was normal.
Hormonal investigations included: follicular
stimulating hormone (FSH) -3.2 IU/mL; leutinizing hormone (LH) - 2.7
IU/mL; and 17
b-estradiol - 64 pg/mL
(increased); thyroid stimulating hormone were normal. 17-OH
progesterone - 2.5 nmol/L, dihydroepiandrostenedione (DHEAS) - 2.2
nmol/L and serum testosterone level - 0.3 ng/mL. Bone age and
estimated by studying the X-ray of the nondominant hand using
Greulich Pyle Atlas, was 7 years.
The entire family was given reassurance and
explained about the etiopathology of precocious puberty in the girl.
They were also counselled in detail about the reversibility of the
condition. The father was advised change of occupation. If it was
not possible, he was advised to use face masks to avoid inhalation
of hormonal dust. He was also asked to change his clothing and to
take bath immediately after returning home from his work place.
The girl was followed up on monthly basis for
eight months. All the changes regressed completely within six
months. Interestingly, the boy also showed regression of
gynecomastia. The father could not find an alternate job and
continued to have gynaecomastia even after eight months.
Discussion
In the present case, the possible mechanism for
premature thelarche and menarche appear to be due to the estrogen
dust which the father was carrying on his clothes from his work
place which was an oral contraceptive manufacturing industry.
Estrogens can be readily absorbed through skin. In the present case,
estrogens might have entered the systemic circulation not only
through absorption from the skin but also through inhalation (in the
case of the father). Prepubertal girls are extremely sensitive to
exogenous estrogens. In the present case, it manifested in the form
of premature menarche and premature thelarche without affecting the
general growth. Similar mechanism might have played its part in the
development of gynecomastia in her brother and father.
It is now understood that nearly every case of
precocious pseudo puberty can secondarily activate the
hypothalamo-pituitary-gonadal axis with development and
superimposition of a central GnRh dependent true precocity process
[1]. Because of this reason, the presence of detectable levels of
FSH and LH is not surprising in the present case.
The linear growth of the body was not affected in
the present case as evidenced by the bone age. Estrogen in low doses
stimulates growth hormone induced Insulin Growth Factor 1 (IGF-1)
secretion of which is responsible for the linear growth. High doses
of estrogen suppresses IGF-1 levels. Another possible mechanism by
which the linear growth is unaffected is that, feedback inhibition
of GnRH by large doses of estrogen. The GnRH plays an important role
in pubertal growth spurt. A similar finding was noted in a previous
study wherein Rhesus monkeys were treated with exogenous
estrogen combination. Premature thelarche and menarche were observed
without any change in the linear bone growth [2].
The highest known incidence of premature
thelarche was observed in Puerto Rico where significant serum levels
of 2 ethylhexyl phthalates and plasticizers were identified as
endocrine disrupting chemicals of estrogenic nature [3]. There are
reports where use of hormone containing hair products like shampoos
and oils had contributed to earlier onset of puberty in the African
American population [4]. Tiwary [5] analyzed that hair products
contained up to 4mg of estradiol per 100gms and he also noted that
the pubertal changes regressed on discontinuing the use of these
products.
A detailed history, examination and
investigations to elicit the etiological factors are of the utmost
importance. Drug ingestion should be suspected in all unexplained
cases of pubertal precocity.
Contributors: HA drafted the manuscript,
investigated the patient, reviewed the literature and is responsible
for the intellectual content. RS helped in the management of the
case. PR helped in the search of literature.
Funding: None.
Competing interests: None stated.
References
1. Speroff L, Feritz MA (eds). Text Book of
Clinical Gynaecologic Endocrinology and Infertility. 7th Ed. New
Delhi: Jaypee Brothers; 2005.
2. Golub MS, Hohrefe CE, Germann SL, Lasky BL,
Nalarajor K, Tarantaly AF. Effect of exogenous estrogenic agents on
pubertal growth and reproductive system maturation in female rhesus
monkeys. Toxicol Sci. 2003;74:103-13.
3. Colon I, Caro D, Bourdony CJ, Rosario O.
Identification of phthalate esters in the serum of young Puerto
Rican girls with premature breast development. Environ Health
Perspect. 2000;108:895-900.
4. Kaplowitz PB, Oberfield SE. Re-examination of
the age limit for defining when puberty is precocious in girls in
the United States; Implications for evaluations and treatment.
Pediatrics. 1999;104; 936-41.
5. Tiwary CM - Premature sexual development in
children following the use of estrogen or placenta containing hair
products. Clin Pediatr. 1998;37:733-9.
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