Endocrinol Japon 1992, 39 (3), 251-257

A Child with Pituitary Gigantism and PrecociousAdrenarche: Does GH and/or PRL Advance the Onset ofAdrenarche?

NORITAKA IWATANI, MIHOKO KODAMA, AND HIROSHI SETO*

Departments of Child Development and *Neurosurgery,Kumamoto University Medical School, Kumamoto 860, Japan

Abstract. We describe a female child with pituitary gigantism and precocious adrenarche. From two

years of age she showed unusual overgrowth, and at 5 years old she was 133.5 cm (+ 5.5 SD) tall andweighed 40.5 kg. Her precocious manifestations were pubic hair, acne vulgaris, hirsutism, and advancedbone age. Endocrinological examination revealed markedly increased serum growth hormone (GH) and

prolactin (PRL), which responded paradoxically to a TRH test. In addition, the concentrations of serumdehydroepiandrosterone (DHA) and its sulfate (DHAS) were increased to adult levels, moving inaccordance with changes in ACTH, which suggested that these androgens were secreted from theadrenal glands functionally. These androgens seemed to be responsible for her partial precocity. Priorreports have suggested that GH and/or PRL overproduction might have played a role in the induction ofadrenarche. Also, in previous reports of 9 gigantism patients under 10 years old, the manifestation of

precocious adrenarche was suggested in 8. Further investigation of the influence of GH and PRL onadrenal androgen production in children with pituitary gigantism is required. On the other hand, inshort children with normal GH secretion, attention should be paid to whether or not the GH therapy inearly childhood induces precocious adrenarche.

Key words: Pituitary gigantism, Precocious adrenarche, GH, PRL, Dehydroepiandrosterone (DHA),DHA sulfate (DHAS). (Endocrinol Japon 39: 251-257, 1992)

LITTLE IS known about the mechanism of theactivation of adrenal androgen secretion in child-hood, referred to as adrenarche. Although the

production of these androgens is stimulated byACTH, ACTH may not be the sole factor regulat-ing adrenarche. Several investigators have sug-

gested that factors other than ACTH are involvedin the control of adrenal androgen production.However, the nature of these agents remains amatter of controversy.

The gigantism child presented here, with pituit-ary adenoma secreting both GH and PRL, wasassociated with precocious adrenarche. GH is amajor hormone promoting linear growth in child-

hood; however, it also has various other biological

effects in vivo. Again, the physiological significanceof PRL is not fully known. Although gigantism

due to pituitary adenoma in childhood is a raredisorder, the patient provides much significant

information for elucidating the biological effectsof GH and/or PRL in childhood. In this report, we

describe in detail the results of endocrinologicalstudies in this gigantism case. Further, we review

previous reports of pituitary gigantism children[1-8], and discuss the still unknown mechanism ofadrenarchal onset.

Subject and Methods

Subject (Case Report)

The subject was a 12.6-year-old girl who was

Received: December 11, 1991Accepted: April 17, 1992Correspondence to: Dr. Noritaka IWATANI, Department ofChild Development, Kumamoto University Medical School,1-1-1 Honjo, Kumamoto 860, Japan.

252 IWATANI et al.

born after 35 gestational weeks of an uncompli-cated pregnancy with a birth weight and length of

2650 g and 46 cm, respectively. Her parents

became aware of her accelerated physical growthat around 2 years of age. At 3.5 years old herheight was 111.0 cm (+4.0 SD) and weight 28 kg

(obesity rate according to height, 49%). She wasfirst admitted to our hospital at 5.4 years old

because of excessive growth. Her physical man-ifestations at that time were: height 133.5 cm (+

5.5 SD); weight 40.5 kg (obesity rate according toheight 36%); a large head (circumference 56.2

cm); a prominent forehead and mandible; a widenasal bridge; thick lips; disproportionately largehands and feet (palm-middle finger length 16.0

cm, and foot length 24.5 cm); and acanthosisnigricans of the axillae. Her heel pad thickness was

27 mm. Other findings at the time were sparse

pubic hair (Tanner grade II) without other exter-nal genital abnormalities, acne on the forehead,hirsutism on the legs, and advanced bone age (7.4

years old); no breast budding or galactorrhea wasobserved. CT scanning of the head revealed anintrasellar tumor extending to the suprasella.

At 5.5 years old, she underwent removal of thetumor under the diagnosis of a GH- and PRL-

secreting adenoma. The pathological diagnosiswas an eosinophilic and chromophobic mixedadenoma. The pituitary tumor, however, was not

resected completely; subsequently 30 Gy irradia-tion and two more surgical operations were

needed at the ages of 6.2 and 9.2 years to remove

the residual tumor. Bromocriptine administrationwas started after the second operation. In spite of

the administration of large doses of bromocrip-tine, serum GH and PRL continued to be abnor-

mally high (Table 1). After the third operationbasal GH decreased to a level slightly higher than

normal, while IGF-I and PRL remained abnormal-ly high (Table 1). She continued to grow excessive-ly tall and heavy.

At the age of 12.6 years, she reached 176.8 cm inheight (+ 4.2 SD) and 86.0 kg in weight, and had

long extremities (upper to lower segment ratio,0.78). Her pubertal signs corresponded to Tanner

grade III for breast and IV for pubic hair, but nomenstruation or galactorrhea was observed. Her

bone age was 13.5 years old at the time.

Methods

To evaluate the pituitary function, provocative

tests were performed during fasting with in-travenous administration of 0.1 U of insulin perkilogram of body weight, 500 ,,cg of TRH and 100

μg of LH-RH. Blood samples were drawn before

and 15, 30, 60, 90 and 120 min after injection. Anoral glucose tolerance test (OGTT) was performedduring fasting with 1.75 g of glucose per kilogramof body weight or 75 g as the maximum dose.Blood samples were drawn before and every 30min after glucose was given, for 180 min. A single

Table 1. Therapy and baseline hormone levels

GH and PRL values indicate means•}1SD (n=number of measured samples). Dose of bromocriptine was

increased from 2.5 to 35 mg/day successively until the third surgery. a, range in adulthood; 1), range in

childhood.

PITUITARY GIGANTISM AND ADRENARCHE 253

dose of 2.5 mg of bromocriptine was administered

orally to assess its influence on serum GH and

PRL, and 7.5 mg of bromocriptine was adminis-

tered for 5 days to assess its influence on

androgens. Dexamethasone was administered in 2,

4, and 8 mg doses for 2 days each to achieve

sufficient suppression of ACTH. An ACTH test

was performed with 250 eug of ACTH-(1-24)

administered intravenously. To assess the changes

in the serum baselines of GH and PRL, serum

samples were obtained at random. Every blood

hormone was measured by means of a specific

RIA: serum GH was measured by a double-

antibody technique (HGH-I kit, Eiken), serum

PRL by an IRMA using monoclonal antibody (Ab

Bead PRL kit, Eiken), serum LH and FSH by a

double-antibody technique (HLH and HFSH kits,

Eiken, respectively), serum cortisol by a solid

phase method (Amerlex-Cortisol kit, Amersham),

TSH by an IRMA with monoclonal antibody

(Amerwell-TSH kit, Amersham), and serum in-

sulin by a solid phase method (Ab Bead Insulin kit,

Eiken). Serum IGF-I was measured by the pre-

viously reported method with an acid-ethanol

extracted sample [9] (SM-C kit, Nichols Institute

Diagnostics), and recombinant IGF-I (Fujisawa

Pharmaceuticals, Japan) was used as the kit's

standard reference. Estradiol, DHA, DHAS, and

etiocholanolone were measured at the Special

Reference Laboratory (Tokyo, Japan). Serum

samples were stored at -20•Ž until use. Adrenal

scintigraphy was performed with 131I-adosterol.

Bone age was estimated by the Tanner-

Whitehouse II method.

Results

During her first and second admissions to our

hospital at 5.4 and 6.0 years of age, detailed

endocrinological evaluations were performed.

Complete blood count, routine blood chemistry,

and thyroid hormone levels were normal, except

for increased alkaline-phosphatase.

The baselines of GH and PRL concentrations in

her serum were markedly increased and the serum

IGF-I level was also very high (Table 1). In

pituitary function studies, serum GH and PRL did

not respond to either insulin-induced hypo-

glycemia or to an LH-RH test. In response to

TRH, however, the GH level rose paradoxically

from 208 to 2513 ng/ml, and PRL increased from

1052 to 1640 ng/ml. A single oral dose of 2.5 mg

bromocriptine resulted in an apparent reduction

in the serum levels of both GH and PRL (from 207

and 858 ng/ml to 39 and 182 ng/ml, respectively).

Serum GH was not suppressed after oral adminis-

tration of glucose. The ACTH-cortisol axis re-

sponded normally to insulin-induced hypo-

glycemia (peak cortisol, 15.3 ƒÊg/dl at 15 min).

Other noticeable findings were increased serum

DHA and DHAS concentrations, already at adult

levels (Table 1), and increased urinary 17-

ketosteroids (17 KS) and urinary etiocholanolone,

one of the metabolites of these androgens. To

determine the origin and nature of these

androgens, an ACTH test, a dexamethasone sup-

pression test, bromocriptine loading, and adrenal

scintigraphy were performed at age 6. In response

to the ACTH and dexamethasone suppression

tests, DHA, DHAS, and etiocholanolone seemed

to move in accordance with changes in ACTH

(Figs. 1 and 2), and the adrenal scintillation

examination showed radioisotope accumulation in

identical positions in bilateral adrenal glands with

a normal image and intensity. These findings

indicated the origin of the androgens to be the

adrenal glands.

In a loading test with 7.5 mg bromocriptine for

5 days, the serum GH and PRL concentrations

remained at abnormally high levels even at the 5th

day (GH: from 82 to 114 ng/ml, PRL: from 519 to

117 ng/m/), and the serum level of DHAS and the

urinary excretion of etiocholanolone were un-

affected (DHAS: from 1072 to 1160 ng/ml,

etiocholanolone: from 2.4 to 2.1 mg/day).

The LH and FSH responses to an LH-RH test

performed at age 5.4 years showed prepubertal

increases (Table 2A). The serum estradiol concen-

Fig.1. Adrenal androgen response to ACTH test. Tested

at age 6. 250 ,ug of ACTH-(1-24) was administered

intravenously.

254 IWATANI et al.

Fig. 2. Dexamethasone suppression test. Tested at age 6.

Dexamethasone was administered orally in doses of

2, 4, and 8 mg for 2 days each. Serum cortisol,DHAS, and urinary etiocholanolone were mea-

sured for 7 days.

Table 2. Pituitary function studies

Examination A was performed at the age of 5.4 years,

and B and C at 12.6 years. Values in parentheses indicate

peak times in minutes.

tration also remained at a prepubertal level (Table1).

At 12.6 years of age, we evaluated her pituitary

function again. Although basal GH had decreasedto a level slightly higher than normal, the serum

GH still showed a paradoxical response to TRHadministration (Table 2C). Furthermore, in an

OGTT, the GH level was not suppressed signi-ficantly, but maintained a slightly higher than

normal level. LH and FSH responded to anLH-RH test better than previously (Table 2B), but

the pituitary-gonadal function did not develop tothe pubertal level because the serum estradiol levelremained below 10 pg/ml (Table 1).

Discussion

The adrenarche, an increase in adrenal

androgens, does not occur in early childhood

[10-12]; however, serum DHA and DHAS of this

patient had already increased to adult levels at 6

years of age. By means of ACTH and dexametha-sone suppression tests performed at 6 years of age,we confirmed that the origin of the androgens,DHA and DHAS, was the adrenal glands, because

the movement of these steroids was dependent onchanges in ACTH (Figs. 1 and 2). Furthermore,

the results of adrenal scintigraphy also indicatedthat the origin of these androgens was the

adrenals.Although DHAS is the most abundant steroid

circulating in the plasma of normal human adults,its biological role is not fully known. Some reportshave suggested that DHAS may possess weak

androgenic and estrogenic activities [13], and that

the adrenarche may be related to the pubic hair

growth [14, 15]. Our patient exhibited the follow-ing noticeable manifestations at 5 and 6 years of

age: pubic hair, acne vulgaris, hirsutism of thelegs, and advanced bone age, which can be

considered a reflection of androgenic and/orestrogenic effects. It seems unlikely that thesefindings resulted from the effects of pituitary-

gonadal axis activation, because gonadotropinresponse to an LH-RH test remained at a pre-

pubertal level and the serum estradiol concentra-tion also remained low (Tables 1 and 2A). There-

fore, increased adrenal androgens should be re-sponsible for her partial precocity and bone age

acceleration.The onset mechanism of adrenarche remains

uncertain. The existence of a pituitary adrenalandrogen-stimulating hormone (AASH), which

acts in the presence of ACTH to stimulate andcontrol the secretion of adrenal androgens, has

been postulated [16-18]. On the other hand, someresearchers do not agree that there is such a factor

and have suggested that adrenarche results from ashift in the pathway of steroid synthesis in re-sponse to the ACTH stimulation that follows the

development of the zona reticularis [19]. However,it is still not known what factor develops the zona

reticularis and causes adrenarche.Does pituitary gigantism associated with preco-

cious adrenarche, as observed in our patient,suggest a relationship between GH and/or PRL

PITUITARY GIGANTISM AND ADRENARCHE 255

and adrenarchal onset? Pituitary gigantism inearly childhood is exceedingly rare, and most

patients show overproduction of both GH andPRL. In our review of the literature, we could findas case reports only nine cases under 10 years oldwho were not associated with McCune-Albrightsyndrome, and eight of the nine reports included adescription of pubertal signs and evaluations of

gonadotropins or steroid hormones [1-8]. Eightout of nine cases, including our patient, exhibited

pubic hair or increased urinary 17-KS withoutother pubertal signs or any gonadotropin or sexhormone increase (Table 3). Unfortunately, ex-cept for our patient, none of their DHA or DHASwas measured, so there was no direct evidence ofadrenarche. However, the findings of pubic hairand urinary 17-KS do not seem to be due to

gonadal activation, and therefore suggest in-creased adrenal androgens. Hence, these clinicalfindings associated with pituitary gigantism indi-cate a possible relationship between GH and/orPRL and the induction of adrenarche.

This possibility is suggested by the following

evidence. Carter et al. [20] and Schiebinger et al.

[21] suggested that hyperprolactinemia was re-sponsible for the stimulation of adrenal androgen

production. They reported that bromocriptineinduced significant decreases in the serum PRL,

DHA, and DHAS concentrations in hyperprolac-tinemic patients. The following observations also

suggest the influence of PRL on adrenal function:adrenal tissue contains PRL receptors [22, 23], and

cultured human adrenal cortical cells exposed toPRL secrete more DHAS than do control cells [24].

GH may also stimulate the growth of the adrenal

glands. Skottner et al. [25] observed augmentationof adrenal weight following their treatment of

experimental rats with GH. Pillion et al. [26] andShigematsu et al. [27] reported that IGF-I receptor

is present in the human adrenal cortex, especiallyin the zona reticularis [26]. Further, in isolated GH

deficient children, adrenarche does occur; howev-er, a lower serum DHAS was observed than in the

control group [28]. These results indicate that PRL

Table 3. Pituitary gigantism under 10 years of age: review of reported cases*

*One case was omitted since it lacked a pubertal evaluation.

Eight out of 9 cases exhibited pubic hair or increased urinary 17-KS without other pubertal signs or any gonadotropin or

sex hormone increase.

u. 17 KS, urinary 17-ketosteroids; E2, estradiol; ND, not described; Ref. no., reference number.a,b, Normal ranges in childhood before adrenarche are below 1-2 mg/day and 3.5 ,u,mol/day, respectively.

256 IWATANI et al.

and also GH, probably mediated by IGF-I, maycontribute to the regulation of adrenal growth andfunction, and as a consequence play a role inadrenarchal onset.

In our patient, to determine the influence of GHand PRL on adrenal androgen secretion, bromoc-riptine was administered for 5 days. It failed,however, to suppress the serum DHAS level oretiocholanolone excretion in the urine probablybecause serum GH and PRL concentrations werenot reduced enough to influence DHAS secretion.As shown in Table 1, despite the reduction in theGH baseline level after the third operation, theblood IGF-I and also the PRL concentrations werestill abnormally high. These findings indicate thatthe residual pituitary adenoma was still active

(Table 2C), and this must be the cause of still highDHA and DHAS levels.

The mechanism of precocious adrenarcheobserved in the gigantism child appears complex.ACTH seems to be necessary to control adrenalandrogen production. Further, the possibility ofthe participation of GH or PRL, or the synergicaction of both, should be considered. Again, it isunclear whether or not GH/IGF-I and/or PRL

contribute to the natural onset of adrenarche.However, the fact that child gigantism with GH-

and PRL-producing adenoma was associated with

precocious adrenarche suggests that GH and/orPRL should be considered a possible causativefactor(s) in adrenarchal onset. Our findings also

invite attention to the GH treatment of shortchildren. The recent unlimited supply of GH

preparation derived from recombinant DNA tech-nology makes possible studies to assess the efficacy

of exogenous GH for height gain in non-GH-deficient short children [29-31], but such a treat-ment may induce precocious adrenarche. Further

investigation of the influence of GH and PRL onadrenal androgen production in children is re-

quired.

Acknowledgments

We thank Dr. Teruhisa Miike, professor of the

Department of Child Development, Kumamoto

University Medical School, for review of the

manuscript and helpful discussion.

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