Human Reproduction Update, Vol.7, No.3 pp.

292±302, 2001

Pathogenesis and epidemiology of precocious puberty.

Effects of exogenous oestrogens

C.-J.Partsch and W.G.Sippell1

Division of Paediatric Endocrinology, Department of Paediatrics, Christian-Albrechts-University of Kiel, Schwanenweg 20, D-24105
Kiel, Germany
1
To whom correspondence should be addressed at: Department of Paediatrics, University of Kiel, Schwanenweg 20, D-24105 Kiel,
Germany. E-mail: [email protected]

Precocious puberty is generally de®ned as the appearance of secondary sex characteristics before age 8 years in girls
(or menarche before age 9 years) and before 9 years in boys. The overall incidence of sexual precocity is estimated to
be 1:5000 to 1:10 000 children. The female-to-male ratio is ~10:1. In addition to the psychosocial disturbances
associated with precocious puberty, the premature pubertal growth spurt (with less time for prepubertal growth)
and the accelerated bone maturation result in reduced adult height. Precocious puberty may be gonadotrophin-
dependent [i.e. of central origin with premature activation of the gonadotrophin-releasing hormone (GnRH) pulse
generator] or gonadotrophin-independent (i.e. peripheral where the GnRH pulse generator is suppressed). This can
be determined by GnRH testing. The pathophysiology is the basis for different diagnostic and therapeutic strategies,
i.e. in the ®rst case a stimulated LH/FSH ratio >1 and suppressive treatment with GnRH agonists (e.g. in
hypothalamic hamartoma), and in the second decreased gonadotrophins and removal or suppression of the
endogenous or exogenous sex steroid source (e.g. congenital adrenal hyperplasia). While several cases of
gonadotrophin-independent precocious puberty due to oestrogen exposure via the transdermal, oral, or inhalative
route have been reported, no case is known with the development of subsequent secondary central precocious
puberty. Food contamination with oestrogens is theoretically possible, but would most probably be sporadic and,
thus, would not lead to precocious puberty. As steroid hormones in meat production are banned in the European
Union, no data on the impact of environmental oestrogenic substances on human maturation are currently available.
In conclusion, the risk for children to develop precocious puberty through exposure to oestrogens (or androgens) in
the environment or in food is very low. Nevertheless, studies of the effects of de®ned environmental oestrogenic
substances on the human reproductive system and on pubertal development are warranted.

Key words: central precocious puberty/GnRH test/hypothalamic hamartoma/oestrogen contamination/precocious pseudopuberty

TABLE OF CONTENTS Introduction

Introduction Precocious puberty is a condition that has a profound impact on
De®nition growth, development and psychosocial well-being of the patient.
Epidemiology From studies of untreated patients the long-term outcome is
Pathophysiology known to include short stature, body disproportion and obesity
Gonadotrophin-dependent precocious puberty (Thamdrup, 1961; Sigurjonsdottir and Hayles, 1968; Sorgo et al.,
Hypothalamic hamartoma 1987). In addition to the long-term physical sequelae of
Secondary central precocious puberty
precocious puberty, there is the potential risk of sexual abuse
Gonadotrophin-independent precocious puberty
due to the premature sexual development (Thamdrup, 1961;
Gonadotrophin-independent isosexual or heterosexual precocious
pseudopuberty due to suspected or proven oestrogen exposure Herman-Giddens et al., 1988). Pregnancies in very young
Food contamination with oestrogens as a cause of precocious children have been described (Stoeckel, 1938; Ehrhardt et al.,
pseudopuberty? 1984). Thus, diagnosis and adequate treatment are of paramount
Acknowledgements importance to ensure normal physical and psychological devel-
References opment of these children. This paper provides an overview of the
pathophysiology and aetiology of precocious puberty with special

292 Ó European Society of Human Reproduction and Embryology

 Pathogenesis of precocious puberty

emphasis on hypothalamic hamartoma as a typical example for secular trend to an earlier age at menarche (median age at
central precocious puberty and on exogenous oestrogens as a menarche 1955: 13.66 years; 1965: 13.40 years; 1980: 13.28
cause of peripheral sexual precocity with possibly increasing years; 1997: 13.15 years) was reported from The Netherlands
frequency. (Fredriks et al., 2000).
In boys, precocious puberty is usually de®ned as gonadarche
(Tanner stage G2 and/or one-sided testicular volume >3 ml) or
De®nition
pubarche (Tanner stage P2) before the 9th birthday. For
Puberty is the period during which human development comparison, normal age for G2 reported in the literature was
progresses from the ®rst pubertal sign to full sexual maturation. 10.8 years (Willers et al., 1996; 50th centile), 11.2 6 1.5 years
Within this period the capacity for reproduction is achieved. (Largo and Prader, 1983a), and 11.6 6 1.07 years (Marshall and
Puberty includes the development of secondary sexual character- Tanner, 1969). Start of pubertal testicular growth in healthy boys
istics as well as growth, development, and maturation of primary de®ned as a one-sided testicular volume of at least 3 ml was seen
sexual organs. Pubertal development that occurs too early is between the ages of 11.8 6 0.9 years (Largo and Prader, 1983a)
de®ned as precocious. Thus, the de®nition of precocious puberty and 12.2 years (Biro et al., 1994). Three and two per cent of
is based on the early age limits for the onset of puberty in the normal boys may show a testicular volume of at least 3 ml and
normal population. Ethnic differences have to be taken into Tanner stage G2 before their 9th birthday, respectively (Largo and
account (Herman-Giddens et al., 1997). Prader, 1983a). In contrast to the trend in pubertal development in
In girls, precocious puberty is most commonly, however, girls, a slight age increase for Tanner stage G2 in boys was seen
arbitrarily de®ned by the appearance of breast development between 1955 and 1997 in The Netherlands (Fredriks et al.,
(thelarche) before the 8th birthday and/or menarche before the 9th 2000).
birthday. These diagnostic threshold ages were derived from
studies of normal pubertal development which showed that
Epidemiology
Tanner stage B2 is present at 10.9 6 1.2 (6 1 SD) years of age in
Swiss girls (Largo and Prader, 1983b) and at 11.2 6 1.1 years in Scienti®cally sound epidemiological data of precocious puberty
British girls (Marshall and Tanner, 1970). Menarche was seen at a are not available in the literature. It is estimated that precocious
mean age of 13.4 6 1.1 years and 13.5 6 1.02 years in the Swiss puberty occurs in 1:5000 to 1:10 000 children (Gonzalez, 1982).
and British girls respectively. Thus, the diagnostic age for In patients with central nervous system (CNS) disorders or CNS
thelarche corresponds to approximately ±2.5 SD below the normal lesions the incidence is much higher. For instance, in neuro®-
mean age while the threshold age for menarche is in the range of bromatosis type I, 2.4-5% of patients develop precocious puberty
±4 SD. From these ®gures it becomes clear that the ages accepted (Habiby et al., 1995, 1997; Cnossen et al., 1997; Carmi et al.,
for diagnosing precocious puberty were chosen somewhat 1999; Virdis et al., 2000), in neonatal encephalopathy the
arbitrarily. Two percent of healthy girls may show a pubertal frequency is 4.3% of girls (Robertson et al., 1990). In patients
stage B2 before their 8th birthday (Largo and Prader, 1983b). A with hydrocephalus the incidence is as high as 10-11% (De Luca
more recent cross-sectional study in paediatric practices in the et al., 1985; Kaiser et al., 1989; Lopponen et al., 1996). Patients
USA (Herman-Giddens et al., 1997) suggested that the onset of with meningomyelocoele have a predisposition for precocious
puberty may be substantially earlier in girls (B2 9.96 6 1.82 years puberty that occurs in 5-18% of affected children (Meyer and
in white American girls) than reported in former studies. Several Landau, 1984; Trollmann et al., 1996). Recently, some congenital
methodological problems of this American paediatric practice dysmorphic syndromes were shown to be associated with an
study have been discussed by the authors themselves (Herman- increased frequency of precocious pubertal development
Giddens et al., 1997) and the major inherent bias is that the (Scothorn and Butler, 1997; Cherniske et al., 1999; Partsch et
patient sample was not randomly selected from the normal al., 1999b).
population.
A recent cross-sectional study of a large number of East
Pathophysiology
German girls investigated between 1984 and 1986 (Engelhardt et
al., 1995) showed that start of puberty (B2: 10.8 years = 50th Normal pubertal development is caused by the increasing
centile, 8.49 years = 3rd centile) and menarche (13.46 years = 50th pulsatile activity of the hypothalamic gonadotrophin-releasing
centile, 11.3 years = 3rd centile) occurred at a very similar age as hormone (GnRH) pulse generator which leads to the maturation
reported in the earlier Swiss and British longitudinal studies of pituitary gonadotrophin release (pulsatile LH and FSH
(Marshall and Tanner, 1970; Largo and Prader, 1983). Thus, at secretion) and subsequently to the maturation of gonads and
least for East Germany there seems to be no trend to an earlier gonadal activity. For the initiation of puberty a functioning GnRH
start of puberty in girls. A recent investigation of menarcheal age neuronal network and pulsatile GnRH secretion are critical
in North German schools has shown a mean age at menarche of prerequisites. The central mechanisms governing GnRH secretion
12.9 years (unpublished observation) which is completely in are located within the neuronal and the glial networks (Ojeda,
accordance with the American data (Herman-Giddens et al., 1994; Ojeda et al., 1995; Terasawa, 1995). To date, it is believed
1997). The question why the length of time between thelarche that two mechanisms are responsible for the central control of
(B2) and menarche was increased in the latter study (2.92 years) pulsatile GnRH secretion: (i) a tonic inhibitory restraint, and (ii)
as compared to all other studies mentioned above (2.3-2.5 years) excitatory inputs to GnRH neurons (Bourguignon et al., 1995).
remains unanswered and may be the consequence of a differing While g-aminobutyric acid (GABA) and GABAA receptors are
patient selection bias at different ages. However, a continuing important components of the tonic inhibitory system, excitatory

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C.-J.Partsch and W.G.Sippell

(Comite et al., 1981; Crowley et al., 1981; Laron et al., 1981;

Roger et al., 1986; Oostdijk et al., 1990; Partsch et al., 1999c), the
treatment of gonadotrophin-independent precocious puberty is
more diverse and highly dependent on the underlying disease.
Gonadotrophin-dependent precocious puberty
For central precocious puberty, estimates of the female-to-male
sex ratio range from 3:1 (Kappy and Ganong, 1994) to 23:1
(Bridges et al., 1994). Central precocious puberty may be
permanent or transient (Table I). The recognition of transient
forms is of particular importance in order not to initiate
unnecessary treatment in these patients (Partsch et al., 1998;
Palmert et al., 1999) and not to attribute outcome results to an
unjusti®ed treatment (Partsch et al., 1999c). It is interesting to
note that in some rare cases organic central precocious puberty
may also be transient (Brauner et al., 1987). Central precocious
puberty does not present as a homogeneous clinical picture, but is
much more a continuum of clinical presentation and rate of
progression ranging from slowly progressive or transient forms to
rapidly progressive forms (Pescovitz et al., 1986; Kreiter et al.,
1993; Partsch et al., 1998; Palmert et al., 1999; LeÂger et al.,
2000).
Until now, even with the use of modern imaging techniques,
Figure 1. Pathophysiology scheme of precocious puberty. CAH = congenital the majority of central precocious puberty patients do not show
adrenal hyperplasia; FMPP = familial male precocious puberty. any CNS lesion or any underlying pathology. This condition is
thus termed idiopathic central precocious puberty. The estimation
of the percentage of idiopathic cases within central precocious
amino acids such as glutamate and its receptor and probably also
puberty varies from 69 to 98% in girls and from 0 to 75% in boys
transforming growth factor (TGF)-a play the major role in the
(Table III). This means that in boys with central precocious
excitatory system (Bourguignon et al., 1995; Ojeda et al., 1995).
puberty the search for an underlying pathology (tumour) needs to
In the case of precocious puberty, this type is called central
be much more rigorous. Furthermore, the likelihood of detecting
precocious puberty as it originates from the central part of the an organic cause of precocious puberty is higher the younger the
feedback loop governing human reproduction. Hormone concen- child. An overview of the various aetiologies is given in Table I.
trations and responses to stimulation tests are consistent with These include a variety of brain tumours and brain malformations.
gonadarche, however, with increased gonadotrophin concentra-
tions relative to the pubertal stage in many patients (Partsch et al., Hypothalamic hamartoma
1989; Oostdijk et al., 1995). Spontaneous LH secretion is Due to improved imaging methodology the number of patients
pulsatile, particularly at night. In analogy to normal puberty, this diagnosed as having a hypothalamic hamartoma is probably
type is also termed `true' or gonadotrophin-dependent precocious increasing. Hypothalamic hamartomas are congenital, non-
puberty (Figure 1, left side). neoplastic tumour-like lesions formed by heterotopic grey matter,
In contrast to the central type of precocious puberty, pubertal neurons, glial cells and ®bre bundles in variable proportions
development may also be caused by the premature secretion of (Inoue et al., 1995). They are usually located at the base of the
sex steroids originating either from the gonads or from other brain at the ¯oor of the third ventricle, near the tuber cinereum or
sources or resulting from exogenous exposure. Thus, the origin of near the mamillary bodies. Since they are congenital malforma-
the hormonal trigger of puberty is not located centrally at the tions, hypothalamic hamartomas frequently cause precocious
GnRH pulse generator but peripherally. It corresponds with the puberty at an early age (Partsch et al., 1999a), sometimes starting
logic of a negative feedback system that central hormonal activity at birth (Albright and Lee, 1992; Guibaud et al., 1995; de Brito et
is suppressed. Therefore, gonadotrophin pulsatility is absent and al., 1999), but may also be asymptomatic (Sato et al., 1985; Arita
responses to GnRH stimulation are low (Figure 1, right side). et al., 1999) or may be found by chance at autopsy (Sherwin et al.,
Since puberty is not the result of the activity of the normal 1962). Some hypothalamic hamartomas are associated with
cascade of hormonal events it is termed precocious `pseudopub- gelastic seizures which may be resistant to anticonvulsive
erty' or gonadotrophin-independent or peripheral precocious treatment (Marliani et al., 1991; Cascino et al., 1993; Nishio et
puberty. al., 1994; Fukuda et al., 1999).
It is important to differentiate between central precocious The incidence of hypothalamic hamartomas in the normal
puberty and the peripheral types of precocious puberty because of population is not known. Recent studies, employing modern
the differences in differential diagnoses (Tables I and II) and techniques of imaging in large series of patients with central
because of the fundamentally different treatment options. While precocious puberty, have shown that hypothalamic hamartomas
medical treatment of central precocious puberty by long-acting are responsible for sexual precocity in 10-28% of these
GnRH agonistic analogues is irrespective of the aetiology children (Lyon et al., 1985: 28%; Hibi and Fujiwara, 1987:

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Table I. Aetiology of central precocious puberty (gonadotrophin-dependent, `true')

Category Underlying disease

Permanent precocious puberty

Idiopathic Sporadic
Familial
CNS abnormalities or lesions Hypothalamic hamartoma
Tumours: astrocytoma, craniopharyngioma, ependymoma, glioma,
LH-secreting adenoma, pinealoma
Congenital malformations: arachnoid cyst, suprasellar cyst, phakomatosis,
hydrocephalus (6 spina bi®da), septo-optic dysplasia
Acquired disease: in¯ammatory CNS disease, abscess, radiation,
chemotherapy, trauma
Dysmorphic syndromes Williams-Beuren syndrome
Klinefelter syndrome (rare)
CNS maturation with central
precocious puberty secondary to
prolonged sex steroid exposure: Congenital adrenal hyperplasia
Sex steroid-producing tumours
Male-limited precocious puberty (constitutively activated LH receptor)
Transient precocious puberty Idiopathic sporadic
Arachnoid cyst
Hydrocephalus
Variants of pubertal development Premature thelarche
(partial or incomplete precocity) Premature pubarche
Premature menarche

14%; Sharafuddin et al., 1994: 11.5%; Kornreich et al., 1995: recently, also, the neurosurgical recommendation is that long-
12.9%; Robben et al., 1995: 10%; Partsch et al., 1999c: 21%). acting GnRH agonists are the ®rst choice of treatment in
Hypothalamic hamartomas contain GnRH-secreting neurons patients with hypothalamic hamartomas and precocious puberty
and it is believed that they function as an accessory GnRH (Stewart et al., 1998; Feuillan et al., 1999; Partsch et al.,
pulse generator outside the physiological feedback loop (Judge 1999a). Successful suppression treatment has been reported by
et al., 1977; Hochman et al., 1981; Price et al., 1984; Culler several groups for a duration of up to 8.4 years (Comite et al.,
et al., 1985; Inoue et al., 1995). However, it has recently been 1984; Mahachoklertwattana et al., 1993; Chamouilli et al.,
shown that TGFa is an important facilitatory component of 1995; Stewart et al., 1998; de Brito et al., 1999; Feuillan et
the central control of puberty (Ojeda et al., 1995) and that al., 1999; Ishii et al., 1999). Long-term studies and outcome
TGFa receptors are expressed in astroglial cells present in data after treatment with GnRH agonists are favourable and do
hypothalamic hamartomas (Jung et al., 1999). Together with not show negative sequelae (de Brito et al., 1999; Feuillan et
other ®ndings concerning the role and function of glial cells al., 1999; Heger et al., 1999). In particular, depot preparations
(Ojeda, 1994) these observations open the possibility that ensure an adult height within the genetic height potential with
precocious puberty in hamartoma patients may be caused by normal body proportions, bone density and reproductive
changes in glial cell activity and by the in¯uence of glial cell function (Heger et al., 1999).
products on hypothalamic GnRH neurons (Jung et al., 1999).
Secondary central precocious puberty
In addition, there are differences in the pituitary response to
exogenous GnRH between patients with hypothalamic hamar- Conditions that lead to long-term exposure to sex steroids and
toma and those with idiopathic precocious puberty suggesting thus to accelerated growth, bone age acceleration and maturation
different changes in the neuroendocrine regulation (Uriarte et of hypothalamic centres important for the initiation of puberty,
al., 1998). Magnetic resonance imaging (MRI) is of particular may lead to secondary central precocious puberty when treated.
importance in the diagnosis of hypothalamic hamartomas since Treatment of the primary disease causes a drop in sex steroid
histological examination will not be carried out in most concentrations and thereby activates the hypothalamic GnRH
patients. The typical MRI picture is that of an isointense pulse generator via the prematurely matured feedback system.
structure on T1-weighted images which may be isointense or This form of precocious puberty may complicate the course of
slightly hyperintense on T2-weighted images. congenital adrenal hyperplasia (Pescovitz et al., 1984; Pouw et
The question of the adequate and optimal treatment of al., 1986; Boepple et al., 1992; Dacou-Voutetakis and Karidis;
children with hypothalamic hamartoma and precocious puberty 1993; Soliman et al., 1997; Frenzel and Doerr, 1998) or familial
has been discussed controversially in the literature (Siegel- or sporadic male-limited precocious puberty (Holland et al., 1987;
Witchel, 1995). In general, however, the paediatric, and Laue et al., 1993; Gromoll et al., 1998; Leschek et al., 1999).

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C.-J.Partsch and W.G.Sippell

Table II. Aetiology of peripheral precocious puberty (gonadotrophin-independent, `pseudopuberty')

Category Underlying disease

Ovarian disorders Granulosa cell tumour

Theca cell tumour
Other oestrogen-secreting tumours: teratoma, teratocarcinoma, dysgerminoma,
luteoma, mixed cell tumour, lipoid tumour
Sex-cord or Sertoli-cell tumour of the ovary with annular tubuli seminiferi
(SCTAT) and aromatase activity in Peutz-Jeghers syndrome
McCune-Albright syndrome (ovarian cysts)
Autonomous isolated ovarian cysts
Testicular disorders Leydig cell adenoma
Constitutively activating LH receptor mutation (male-limited precocious
puberty = testotoxicosis)
Adrenal disorders Adrenal adenoma
Adrenal carcinoma (usually virilizing)
Congenital adrenal hyperplasia (21-hydroxylase or 11b-hydroxylase de®ciency)
HCG-secreting tumours Dysgerminoma, teratoma, chorioepithelioma, choriocarcinoma, hepatoblastoma,
pinealoma
Exogenous Sex steroid exposure: pills (oestrogens; anabolics), food additives, cosmetics,
creams etc.
Transient precocious
puberty Autonomous isolated ovarian cysts (self-limiting)
Exogenous (interruption of exposure)

HCG = human chorionic gonadotrophin.

Table III. Frequency (%) of idiopathic forms of central precocious puberty (excluding secondary central
precocious puberty) in girls and boys. Precocious puberty was de®ned as start of pubertal development before
age 8 years in girls and before age 9 years in boys.

Reference Idiopathic central precocious puberty (%)

All Girls Boys

Thamdrup (1961) 67.9 75.6 36.4

n = 56
Pescovitz et al. (1986) 57.9 69 10
n = 107
Kaplan and Grumbach (1990) 65.4 72.9 33
n = 205
Brauner and Rappaport (1993) 62.6 70.1 28.3
n = 294
Bridges et al. (1994) 89.5 93.4 0
n = 95
Kappy and Ganong (1994) 61.6 74 28
n = 640
Carel et al. (1999)* 95.5 98 75
n = 66
Heger et al. (1999) and Partsch et al. (1999b) - 73.3 -
n = 90
Cisternino et al. (2000) - 74.4 -
n = 304
De Sanctis et al. (2000) - - 60
n = 45

*De®nition of precocious puberty in boys: start of puberty <10 years of age.

Secondary central precocious puberty has also been described in al., 1986; Schmidt and Kiess, 1998; Feuillan et al., 1993). In the
single patients with the McCune-Albright syndrome (Kaufman et literature there is one single case of transient central precocious

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 Pathogenesis of precocious puberty

Table IV. Precocious pseudopuberty (gonadotrophin-independent) in children after ingestion or dermal exposure to oestrogen-containing food or ointments

Reference n/sex Age (years)/ Plasma Mode of Substance

breast oestradiol exposure and dose
stage (B) (pg/ml)

Hesselvik (1952) 1/m 0.8/B3 - Transdermal DES

Prouty (1952) 1/m 4/B3 - Transdermal DES (dust from tablet-
+ inhalation making machine)
Cook et al. (1953) 2/f 4±7/B2±3 - Ingestion DES (2 mg/day for 4 weeks)
Green (1958) 2/1f + 1m 2±3/B3 - Ingestion + DES (pellets and paste on
transdermal poultry farm)
Hertz (1958) 4/1f + 3m 5±10/B2 - Ingestion Oestrone/150 mg per day
Weber et al. (1963) 7/4f + 3m 1.7±8.6/ UE Ingestion DES contamination of INH
B2±3? undetected tablets (12±90 mg/day)
Landolt and MuÈrset 4/1f + 3m 0.25±9/B2-3 - Transdermal DES in hair lotion or
(1968) + ingestion ointment (25±250 mg/child)
Beas et al. (1969) 7/3f + 4m 0.3±2/B2±4 - Transdermal Oestrogenic effect
equivalent to 0.1 mg
oestradiol benzoate
Fara et al. (1979) 323/110f 3±14/B2 Slightly Ingestion? Oestrogens in uncontrolled
+ 223m increased poultry and beef?
Ramos and Bower 1/f 3.3/B2 UE Transdermal Oestrogens in facial cream
(1969) 4 mg/24 h (2500 units/6 months)
Kimball et al. (1981) 8/7f + 1m B2±3 - Ingestion? Oestrinyl in cow's milk?
Edidin and Levitsky 1/m 5/B3 114 Hair cream 1.01 mg `natural' oestrogens
(1982) per 2 oz jar hair cream
Pasquino et al. (1982) 3/f 0.75±7/B2 <10 Ingestion? Not clari®ed (oestrogen-
contaminated meat
suspected)
HalpeÂrin and 1/m 6.5/B3 14 Transdermal Oestrone, diethylstilboestrol,
Sizonenko (1983) extracts of ovaries
Freni-Titulaer et al. 120/f 0.5±8/B2 - Not known No risk factors or substances
(1986) found
Nizzoli et al. (1986) 73/45f + 1±2/B2 - Not known No risk factor found
28m besides residence in Milan
Peter et al. (1995) 1/f 2/B2±3 20 Transdermal 330 mg 17b-oestradiol/day
Zimmerman et al. 8/- -/- Normal Transdermal Oestrogens in hair care
(1995) products
Tiwary (1998) 4/f 1±7.5/B1±3 6 Transdermal Oestriol (16±20 mg/g),
17b-oestradiol (0.04 mg/g)
in hair products
For comparison:
Illig et al. 9/f 11.7±14.4/ 6.8 6 1.7 - No therapy
(1990) UTS B1®2 14 6 7.1 Transdermal 5 mg 17b-oestradiol/day
B2®5 20 6 11.6 Substitution 10 mg 17b-oestradiol/day
B3®5 54 6 26.3 Treatment 25 mg 17b-oestradiol/day

UTS = Ullrich-Turner syndrome; 17b-oestradiol = 17b-oestradiol; f = female; m = male; DES = diethylstilboestrol; INH = isonicotinic acid hydrazide;
UE = urinary oestrogens.

puberty secondary to non-classic 21-hydroxylase de®ciency Gonadotrophin-independent isosexual or heterosexual precocious

(Speiser, 1995) pseudopuberty due to suspected or proven oestrogen exposure
In prepubertal children, increased oestrogen intake or exposure
Gonadotrophin-independent precocious puberty
may lead to precocious pubertal development which is isosexual
An overview of the various aetiologies is shown in Table II. in girls and heterosexual in boys. Main symptoms are breast
Gonadotrophin-independent precocious puberty can originate development, hyperpigmentation of areolae, of linea alba, genitals
from the gonads, the adrenals, from extragonadal or intragonadal and skin folds, and in girls, in addition, vaginal discharge and
sources of human chorionic gonadotrophin, or from exogenous menstruation. The ®rst cases described were due to diethylstil-
sources. The majority of cases of gonadotrophin-independent boestrol (DES) exposure (Hesselvik, 1952; Prouty, 1952; Cook et
precocious puberty are permanent; however, in some instances it al., 1953; Green, 1958; Weber et al., 1963; Landolt and MuÈrset,
also may be transient (e.g. autonomous ovarian cysts with self- 1968; HalpeÂrin and Sizonenko, 1983; Table I). Routes of
limiting activity). incorporation were transdermal (Hesselvik, 1952; Prouty, 1952;

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C.-J.Partsch and W.G.Sippell

Table V. Potential contamination of meat with 17b-oestradiol (ng steroid Two epidemics of premature onset of puberty are of particular
hormone per kg tissue) interest. The ®rst was noted at Italian schools between 1977 and
1979 (Fara et al., 1979; Scaglioni et al., 1978). An apparent
Animal Content of 17b-oestradiol found in animals (ng/kg tissue) outbreak of breast development involving several hundred
children was seen at a school in Milan (Fara et al., 1979;
Muscle Liver Fat Scaglioni et al., 1979). Plasma oestradiol concentrations were
Calf, untreated 0.11 6 0.14 0.07 6 0.16 0.13 6 0.06
slightly elevated. The clinical picture was mild; usually breast
Cow, pregnant 32.7 6 16.1 1027 6 365 67.6 6 34.6 enlargement was Tanner stage 2. A source of oestrogen was not
Heifer, treateda 10.7 6 5.1 3.2 6 2.4 49.3 6 30.8 identi®ed, however, the uncontrolled supply of poultry and veal
putatively contaminated with oestrogens was suspected to be the
Data are given as mean 6 SD. origin of the problem (Fara et al., 1979). In Italy a surprisingly
a
Treatment with implant containing 200 mg testosterone propionate and 20 high number of baby food made of homogenized veal was found
mg oestradiol benzoate (Bundesinstitut fuÈr Gesundheitlichen to have oestrogenic activity and to contain DES (Loizzo et al.,
Verbraucherschutz und VeterinaÈrmedizin, 1999). 1984). However, the number of contaminated baby food samples
decreased to zero between 1980 and 1982. As older children were
Green, 1958; Landolt and MuÈrset, 1968; Beas et al., 1969; Ramos also affected, the contamination of baby food could not explain
and Bower, 1969; Edidin and Levitsky, 1982; HalpeÂrin and the whole epidemic. A surprisingly high prevalence of premature
Sizonenko, 1983; Peter et al., 1995; Tiwary, 1998), oral ingestion thelarche (21.1% of 1-2 year old girls) and gynaecomastia (36.6%
(Cook et al., 1953; Green, 1958; Weber et al., 1963; Landolt and of 1-2 year old boys) was found in northern Italy (Nizzoli et al.,
MuÈrset, 1968; Fara et al., 1979; Kimball et al., 1981), and even 1986). The highest numbers were reported from Milan. However,
inhalation (Prouty, 1952). In some cases, however, the source of statistical analysis did not show a signi®cant factor associated
the exposure to exogenous oestrogen remained obscure (Kimball with the clinical signs.
et al., 1981; Pasquino et al., 1982; Freni-Titulaer et al., 1986; The second, even larger, epidemic was reported from Puerto
Nizzoli et al., 1986). Over the years several additional cases Rico (PeÂrez Comas, 1982). Initially, more than 500 children were
resulting from substances other than DES have been reported examined over a 7 year period for signs of precocious pubertal
(Table IV). In most cases children had come into contact with development (PeÂrez Comas, 1982; Saenz de Rodriguez et al.,
ointments, creams, hair tonics or tablets from other household 1985). The majority presented with premature thelarche, but a
members. Contamination of a prescription drug with DES due to a considerable number (n = 158) showed additional signs of
maturational advancement (Saenz de Rodriguez et al., 1985).
manufacturing problem (improperly cleaned tablet-making ma-
Food contamination with oestrogenic substancesÐthe ®rst
chine) caused a small outbreak of precocious pseudopuberty in
suspect was DESÐand with naturally occurring phyto-oestrogens
two hospitals (Weber et al., 1963). Plasma oestradiol concentra-
have been implicated as causing the epidemic (Schoental, 1983).
tions were highly variable. A low plasma oestradiol did not
However, to date, no single substance was found in food samples.
exclude oestrogen-induced development of secondary sex char-
In a case-control study, signi®cantly positive associations were
acteristics. Exposure to exogenous oestrogens has to be ruled out
found for children below 2 years old between premature thelarche
with great care to avoid unnecessary laparotomy (Cook et al.,
and the consumption of soy-based formula and of various meat
1953). The importance of the topic of oestrogen contamination
products (Freni-Titulaer et al., 1986). However, in more than 50%
has been con®rmed by the ®nding of a high usage frequency of
of the case subjects, no exposure to any of the risk factors was
hair care products which contained oestrogens (7.8%) in a series present. Thus, the value of the statistical analysis remained
of 102 children with sexual precocity (Zimmerman et al., 1995), questionable. Furthermore, a dose-response effect was not taken
and by a report on four girls using hair products which contained into account (Montague-Brown, 1987). In a recent status report
hormones or placenta (Tiwary, 1998). These authors pointed out from Puerto Rico (Perez-Comas et al., 1991) more than 3000
the importance of extremely thorough questioning of the parents cases were collected. Although the results of clinical and
and of actually looking at the labels and the products used in the laboratory studies and the protective effect of certain diets
patients' homes. The dose of oestrogen the children were exposed provided evidence for an oestrogenic contamination of food, no
to could not be determined in most cases (Table IV). However, a de®ned substance could be identi®ed to date.
maximal daily exposure to 330 mg oestradiol was suspected (Peter
et al., 1995). For comparison, the induction of puberty in girls Food contamination with oestrogens as a cause of precocious
with Ullrich-Turner syndrome can be achieved by the transdermal pseudopuberty?
administration of increasing doses of 5-25 mg 17b-oestradiol/day The Italian and Puerto Rican precocious puberty epidemics have
(Illig et al., 1990). It is therefore not surprising that the girl with drawn attention to the question as to whether the induction of
the oestrogen exposure to 330 mg/day showed all signs of precocious puberty is theoretically possible by the ingestion of
precocious puberty including bone age acceleration (Peter et al., oestrogen-contaminated meat or meat products. What is an
1995). However, it must be stressed that in contrast to patients acceptable and safe intake of oestrogens from exogenous sources
with congenital adrenal hyperplasia, familial male-limited for children? A guideline from the US Food and Drug
precocious puberty or McCune-Albright syndrome, no patient Administration de®nes an additional intake of not more than
has been reported in whom secondary central precocious puberty 1% of the normal daily oestrogen production rate of prepubertal
developed after precocious pseudopuberty due to exogenous children as safe (US Food and Drug Administration, 1999). Thus,
oestrogen exposure. the calculation of the excess daily oestrogen intake depends on the

298
 Pathogenesis of precocious puberty

Table VI. Excess dietary intake of 17b-oestradiol (ng/person per day) treatment and on the animal used (Table VI). The manufacturing
calculated on the basis of a standard diet consisting of 300 g muscle, 100 g process of meat products has no in¯uence on the structure and
liver, 50 g kidney and 50 g fat per day (Joint FAO/WHO Expert Committee on
concentration of steroid hormones present in animal tissues
Food Additives, 1988a,b)
(Fritsche and Steinhart, 1999; Karg and Meyer, 1999) and is
therefore no safeguard against oestrogen ingestion. The estimated
Excess intake with WHO/JECFA standard diet (ng/person/day) daily consumption of 100 g meat (calculated for muscle) may
Bull, treated -1.0 to +0.9 result in an intake of a maximum of 1600 ng oestradiol per day in
Ox, treated -0.4 to +47
Heifer, treateda +2.8 to +6916
a child (Bergner-Lang et al., 1989; Table VI). This intake would
Cow, pregnant +465 clearly be in excess of the FDA guideline. The worst-case
Calf, treatedb +4753 to +4783 scenario of a complete hormone implant ®nding its way into a jar
Estimated intake for a child (ng/100 g meat/day) of baby food leads, of course, to an exorbitantly high oestrogen
Calf, untreated 3±11 exposure. Thus, it seems possible for children to be exposed to a
Calf, treatedb 1600 signi®cant amount of oestrogens through food consumption.
Heifer, untreated 0±3
Heifer, treateda 0.6±1010
However, in order to cause precocious pseudopuberty, this
Ox, untreated 0.1±0.7 exposure would have to be constant over a time period of some
Ox, treated 1±6 months, which is very unlikely. To our knowledge, there are no
Worst case scenario = total steroid 20 mg oestradiol benzoate reports in the literature showing that precocious pseudopuberty
implant in one jar of baby food was the consequence of a proven exposure to oestrogen in food.
The signs that might be expected from a moderate but prolonged
In the lower half of the table, 17b-oestradiol intake calculated for a child oestrogen exposure are other than precocious puberty and have
with the daily consumption of 100 g muscle meat is shown (minimal and been reviewed recently (Andersson and Skakkebaek, 1999).
maximal values).
a
Treatment with implant containing 200 mg testosterone propionate and 20 Although there is concern that oestrogen consumption through
mg oestradiol benzoate. food might have adverse effects on pubertal development and
b
Treatment with implant containing 200 mg testosterone and 20 mg 17b- even human health, there are no published data to support the
oestradiol (Bundesinstitut fuÈr Gesundheitlichen Verbraucherschutz und
notion that an increased overall exposure to environmental
VeterinaÈrmedizin, 1999).
oestrogens has led to an increased incidence in precocious
puberty or to an earlier start of pubertal development.
normal daily oestrogen production rate for prepubertal girls and
boys. This was reported to be 6 mg 17b-oestradiol per day for Acknowledgement
prepubertal boys (Joint FAO/WHO Expert Committee on Food
Additives, 1988a). However, this estimate has been criticized The authors are grateful to Joanna Voerste for linguistic help with the
manuscript.
regarding the relatively insensitive methods for the measurement
of plasma oestradiol and the calculation of the oestradiol
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