Precocious puberty in juvenile hypothyroidism

January 1978 The Journal o f P E D I A T R I C S

55

Precocious puberty in juvenile hypothyroidism Three children, two girls and one boy, presented with hypothyroidism and precocious sexual development. Serum T S H and P R L were elevated in all cases. In the male patient, pituitary stimulation with T R H produced exaggerated T S H and P R L responses. Elevated serum LH, FSH, estrone, estradiol, and an attenuated gonadotropin response to GnRH were documented in the male patient and in one o f the female patients. Serum testosterone was elevated for age in one o f the female patients but prepubertal in the male patient. After treatment with L-thyroxine, elevated hormonal levels decreased to normal in one patient who returned for follow-up, Evidence is presented that precocious puberty in juvenile hypothyroidism may be the result of P R L hypersecretion.

Zuhayr S. Hemady, M.D.,* Boston, Mass., Theresa M. Siler-Khodr, Ph.D., San Antonio, Texas, and Samir Najjar, M.D., Charlottesville, Va.

PRECOCIOUS PUBERTY is a known, albeit unusual, manifestation of juvenile hypothyroidism. In 1905, Kendle 1 was the first to draw attention to this entity and as late as 1972, only 22 similar instances had been recorded? Recently, Barnes and associates, 3 after reviewing the Mayo Clinic cases, concluded that precocious sexuality is a c o m m o n feature of severe juvenile hypothyroidism provided bone age is taken as the true index of maturation. The pathogenesis of this association remains a matter of controversy and m a n y unanswered questions await further understanding of the complex endocrine interactions involved. It is the purpose of this report to describe three cases of juvenile hypothyroidism with sexual precocity. The implications of the clinical and laboratory findings to the underlying pathophysiology are discussed. CASE REPORTS Case 1. Patient L. A. K., a 3-year-old Pakistani girl, was admitted to the American University Hospital because of vaginal bleeding of 6 months duration. Since birth she was noted to be From the Departments o f Pediatrics and Obstetrics and Gynecology, American University o f Beirut Medical Center. *Reprint address: Division of Endocrinology, The Children's Hospital Medical Center, 300 Longwood Ave., Boston, MA 02115.

slow and apathetic. Growth and development were severely delayed and she could only say single words. She had chronic constipation. Eleven months prior to admission the parents noted enlargement of the breasts and growth of some pubic hair. A physician diagnosed hypothyroidism and prescribed a thyroid preparation which she received for 12 days only. Six months prior to admission she had an episode of profuse vaginal bleeding which continued for five days. Thereafter several episodes of vaginal bleeding were noted. On physical examination the patient had a typical hypothyroid facies, dry skin, and a hoarse Abbreviations used TSH: thyroid-stimulating hormone PRL: prolactin LH: luteinizing hormone FSH: follicle-stimulating hormone El: estrone E2: estradiol A: androstenedione T: testosterone T4: thyroxine TRH: thyrotropin-releasing hormone GnRH: gonadotropin-releasing hormone GH: growth hormone ACTH: adrenocorticotropic hormone voice. Height was 78 cm (height age 14/12years) and weight was 10.5 kg. The head circumference was 45 cm. She had no goiter. Breast tissue was definitely palpable bilaterally, and milk was expressed upon pressure. The abdomen was soft and two nontender cystic movable masses could be felt in the lower

Vol. 92, No. 1, pp. 55-59

56

Hemady, Siler-Khodr, and Najjar

The Journal of Pediatrics January 1978

Table I. Serum h o r m o n a l c o n c e n t r a t i o n s before a n d after t r e a t m e n t of three h y p o t h y r o i d children

Patients S.S. L. A.K. A.D. A.D.

Therapy None None None 200 ~g L-thyroxine for 2 mo

T4 TSH (l~g/dl) I(l~U/ml)I

PRL (ng/ml)

1.8 2.8 2.3 6.2

540 2,050 620 10

53 250 74 26

Normal adults

4-12

<8.0

Normal preadolescents

4-12

<8.0

13.5 • 0.9 (males) 18.0 ~+ 0.921 (females) <15 ==

LH FSH I E1 (mlU/ml) (mlU/ml) (pg/ml) 33 3l 10

26 18 3.0

501 348 < 79

A

T

(pg/ml)

(pg/ml)

(pg/ml)

275 257 < 22

238 <147 90

255 <111 < 57

E2

70 +_+ 13~'* 56 _+ 27 ~* (females) (females)

< 5 =~

< 5 =~

1923 • 66 ~ 370+_ 14~t (females) (females)

<500 ~'

< 1002~

*Values were obtained during cycle days 2-4 of menstrual cycle. ]'Values were obtained at midcycle. quadrants: the right measured 9 x 5 cm and the left, 1 • 3 cm. The labia majora and minora were well developed; the latter were hyperpigmented. The vaginal mucosa was pink, boggy, and moist. There were about 50 thin pubic hairs. Rectal examination revealed bilateral parautefine masses, the right larger than the left, and a well-developed uterus. A vaginal smear showed estrogenic effect. The bone age was estimated at 9 months according to the Greulich and Pyle standards. Gynecography revealed bilaterally enlarged ovaries. The patient was discharged on dessicated thyroid. Her father wrote a year later that the signs and symptoms of hypothyroidism and sexual precocity disappeared after thyroid replacement and that she was doing well. Case 2. Patient S. S,, an 8-year-old Syrian girl, presented to the American University Hospital with psychomotor retardation and chronic constipation of several years duration. On physical examination she was a dull-looking girl with cretinoid facies. She had a hoarse voice and an open anterior fontanelle. She was 90 cm in height (height age 24/12years) and weighed 15.1 kg. The skin was dry and scaly. The thyroid gland was not palpable. The breasts were enlarged. She had a protuberant abdomen with an umbilical hernia, but no masses were felt. Examination of the genitals disclosed a pink and boggy vaginal mucosa with some enlargement of the labia minora; there was no pubic hair. Her calf muscles were hypertrophied. Bone age was estimated at one year according to the standards of Greulich and Pyle. A vaginal smear showed estrogenic effect. Dessicated thyroid was presci"ibed, but the patient was lost to follow-up. Case 3. Patient A. D., a 14-year-old boy, presented to the American University Hospital with the chief complaint of short stature. He developed normally in the first five years of" life, but his growth rate decreased markedly thereafterl He tended to be less active than his peers but he did well in school. He had delayed teething, ' but no definite history of constipation, cold intolerance, or anorexia. On physical examination, his height was 120 cm (height age 69/12years) and weight was 25.5 kg. He hai] mottled dry skin, an immature-looking facies, and a carotenemic hue. The thyroid gland was not palpable. The abdomen was distended and he had hypertrophied calf muscles. Each' testis measured 3l/z x 21/2 cm; there was scanty thin pubic hair. Bone

age was estimated at 36/12 years by the Greulich and Pyle standards. The patient was discharged on L-thyroxine, 0,2 rag/ day, and was seen again four months after the initial diagnosis at which time he had grown 5 cm in height. The testes were unchanged in size.

MATERIALS

AND METHODS

Basal levels ofT~, TSH, PRL, LH, F S H , E,, E~, A, a n d T were o b t a i n e d from each p a t i e n t prior to the initiation o f thyroid treatment. After treatment, s e r u m T~, TSH, PRL, LH, F S H , El, E2, A, a n d T were r e p e a t e d on Patient A. D. only. T h e pituitary responses to G n R H a n d / o r T R H were d e t e r m i n e d in Patients L. A. K. a n d A. D. Each p a t i e n t was studied after a n o v e r n i g h t fast a n d at b e d rest. Blood samples for s e r u m TSH, PRL, LH, a n d F S H were obtained from a n indwelling i n t r a v e n o u s catheter. Patient L. A. K2 received 33 ttg of G n R H as an i n t r a v e n o u s bolus; blood samples were o b t a i n e d at 0, 15, 30, 60, a n d 90 minutes. Patient A. D . was given a 200 /xg i n t r a v e n o u s bolus of T R H followed 105 m i n u t e s later by a 100 /~g i n t r a v e n o u s bolus o f G n R H . Blood samples were o b t a i n e d at 0, 15, 30, 60, and 90 m i n u t e s following the administration of T R H a n d G n R H , respectively. S e r u m TSH, PRL, LH, FSH, El, E2, A, a n d T were d e t e r m i n e d b y i m m u n o a s s a y as previously describedr -6 The degre e o f cross reaction with T S H in the L H a n d F S H assays was less t h a n 0.001%. All samples f r o m a single study were r u n in the same assay. S e r u m T~ m e a s u r e m e n t s were p e r f o r m e d by d i s p l a c e m e n t using R e s - O - M a t Kits (Mallinkrodt).

RESULTS T h e serum h o r m o n a l c o n c e n t r a t i o n s before (all patients) a n d after (Patient A. D. only) thyroid r e p l a c e m e n t for the three patients are s h o w n in T a b l e I. Basal levels of

Volume 92 Number 1

Precocious puberty in hypothyroidism

LH

~x---~ FSH TRH

"~

. ~/~'"--"

-" ~ - ~ - ' ~

2

40

~ PRL o---o TSH

GnRH ~

_-

E

20

~..A._.~

.......

A .......

A..a....'~"-~

........

a .......

a

.I--Iu.

c/) ,.I

u. 0

_

LH A---.z~FSH

6O

GnRH

40

E u~-J3:: 3::

H PRL o---o T S H

57

L

i

i

}

i

i

i

i

i

i

20 0 300

2 0 0 ] ~ TRH ~

GnRH

I

I

I

I

I

Gn~,~

25(}

20(} 0/

I

I

I

I

I

2000 [

I

I

I

I

I

GnRH

C .J II: CL

loc

'~176176176 ........................ .... o

0|

o

......... 01 , 250(} -GnRH

I

I

I

0

15

30

I

60

I

I

I

I

9 0 105 120 135

I

I

165

195

200(}

MINUTES

Fig. 1. LH ( n ~ ) , FSH (A. . . . a), PRL ( H ) , and TSH (o- - -o) responses to sequential intravenous administration of TRH and GnRH in Patient A.D.

.......

--'0

"1" I--

100(}

[

60

serum PRL, LH, FSH, El, and E2 were well above the prepubertal range, whereas basal levels of plasma A were in the prepubertal range in both female and male patients. Basal serum T was in the female pubertal range in Patient L. A . K:; it was in the prepubertal range in Patient A. D. Serum TSH was elevated markedly in all patients. The increase in serum PRL level was greatest in the patient With the highest elevation of TSH and the greatest degree Of precocity. The TSH, PRL, LH, and FSH responses to TRH and/ or GnRH stimulation in Patients A. D. and L. A. K. are illustrated in Figs. 1 and 2. Patient A. D. had a twofold increase in serum TSH within 30 minutes after TRH administration, a n d this level was sustained with only minor fluctuations for 135 minutes. Following GnRH injection, serum TSH rose to a peak of 1,400/xU/ml at 15 minutes in Patient A. D. but did not change significantly in Patient L. A. K. The basal serum PRL level in Patient A. D. increased from a baseline level of 74/~U/ml to a peak level of 140 n g / m l 15 minutes following the injection of TRH. There was n o significant change in the basal serum PRL level following injection of GnRH in each patient studied. Slight but statistical!y significant ( > 2 SD of replicates) fluctuations in gonadotropin concentrations were observed after TRH administration to Patient A. D. Following GnRH administration to this patient, there was, however,'a small but insignificant increase in LH and FSH. In Patient L. A. K. there was a slight and barely significant increase in LH 30 minutes after the GnRH injection, but no significant change in FSH was observed.

0

150C

J

90

MINUTES

Fig. 2. LH (A--A), FSH (A. . . . A), PRL (~, e,), and TSH (o . . . . o) responses to intravenous administration of CmRH in Patient L. A. K. After treatment,, the elevated basal serum hormone levels in Patient A. D. decreased toward normal prepubertal ranges. DISCUSSION Our three cases of precocious sexual development associated with juvenile hypothyroidism had longstanding severe thyroid failure in association with highly elevated basal serum TSH levels. Hyperproduction of TSH was accompanied by a striking elevation of basal serum PRL levels in the female patient with galactorrhea (Patient L. A2 K.) as a more than twofold increase above normal adult !evels in the two other patients with less advanced sexu M precocity. Previous repocts have shown that serum PRL and TSH concentrations may be elevated in hypothyroid patients with and without clinical evidence of precocious puberty. 7' ~ In addition, our data suggest that the magnitude of serum PRL elevation corresponds to the degree of sexual development and is proportional to the increase in TSH values. Pituitary stimulation with TRH resulted in an augmented absolute (ATSH) but not relative (percentage increment above basal level) TSH response as compared to normal prepubertal subjects. The absolute prolactin response (APRL) following TRH stimulation was greater

58

Hemady, Siler-Khodr, and Najjar

than the response observed in normal prepubertal subjects. 7~ These findings imply that an increase in pituitary storage of both TSH and PRL occurs in this condition and is reflected by elevated basal levels. Basal FSH and LH levels were well above the prepubertal range and confirm previous reports of increased secretion of gonadotropins in this syndrome) A very small increase in LH and FSH concentrations was observed following the administration of GnRH. Whether these slight changes in serum gonadotropins are due to pulsatile fluctuations or to a specific pituitary response to GnRH cannot be answered. In addition, the abnormally attenuated FSH and LH response to GnRH stimulation in our patients may indicate depletion of the readily releasable pituitary reserve of gonadotropins in contradistinction to the situation in children with true precocious puberty? An interesting finding in-our study is the profile of the sex steroids. The basal serum E, and, to a lesser extent, serum E~ were elevated for age and stage of sexual development in both female and male patients while serum T was in the adult range only in the female patient. In the two hypothyroid girls, there was obvious clinical evidence of estrogen excess manifested by breast enlargement, estrogenization of the vaginal mucosa, and even vaginal bleeding in the more severely affected child. Growth of pubic hair however, lagged behind other signs of sexual maturation. Similarly, in the male patient studied, testicular size was at a more advanced stage of puberty than the sparse pubic hair observed. This lack of peripheral manifestations of androgenic stimulation seems to be a characteristic feature of this type of precocious puberty? Although the underlying pathophysiology of this unusual association is still largely unknown, several pathogenetic mechanisms have been considered. Maturation of the hypothalamic-pituitary axis as occurs in true precocious puberty is unlikely since the precocious sexual manifestations are reversible. In addition, the lack of a pituitary response to acute stimulation with exogenous LRH in our patients further suggests that endogenous L R H stimulation of pituitary gonadotrophs does not contribute to the elevation of circulating LH and FSH. An overlap in the hormonal feedback mechanism at the hypothalamopituitary level that resulted in an overproduction of multiple pituitary hormones was postulated by Van Wyk and Grumbach? ~ As evidence of nonspecific overproduction of pituitary hormones, enlargement of the sella turcica may occur in this syndrome? However, the fact that some tropic hormones such as GH and ACTH do not seem to be produced excessively~ is not in keeping with this hypothesis. A derangement in metabolism of the sex steroids secondary to deficiency of thyroxine has also

77w Journal of Pediatrics January 1978

been mentioned as a possible pathogenetic mechanism. '2 The exact influence of the hypothyroid state on sex steroids and particularly on estrogen metabolism, however, is not well defined. More recently, Barnes and associates~ advanced the hypothesis that hypersecretion of PRL is the primary etiologic factor leading to precocious sexual development in this condition. The fact that the degree of PRL elevation was proportionate to the extent of sexual maturation in our three patients is consistent with this hypothesis. Of further interest in this regard is the recent report of re-establishment of normal reproductive function in adult hypothyroid women solely with a potent inhibitor of PRL release (Bromocryptine) while hypothyroidism persists. 1:' Data from animal studies may also support this mechanism. In rats, the implantation of PRL either subcutaneously or in the median eminence increases serum gonadotropins and significantly advances the onset of puberty. ~-~ The abnormal serum concentrations of sex steroids in our patients (resulting in elevated estrogens in both Patients L. A. K. and A. D. and elevated testosterone in Patient L. A. K.) may be related to hypersecretion of PRL. Evidence for a direct action of PRL on the ovaries can be inferred from in vitro studies on the human follicle~ and from in vivo studies on untreated hypothyroid women with amenorrhea-galactorrhea ~:~ as well as on normal female volunteers2 ~ In hypothyroid male patients with oligo- or azospermia despite normal plasma gonadotropins, hyperprolactinemia has been implicated in the pathogenesi s of hypogonadism2 ~ In addition, PRLproducing tumors induced hypogonadism and low testosterone levels in male rats. 19 On the basis of the above data and available evidence in the literature, we would like to advance the following pathogenetic hypothesis: In juvenile hypothyroidism with precocious puberty, an elevated serum PRL has a direct effect on gonadal steroidogenesis and results in elevated serum estrogens. In the male it may stimulate tubular development while it inhibits production of testosterone in Leydig cells. Hyperprolactinemia either directly and/or indirectly via the elevated serum estrogens .-'~causes release of LH and FSH from the pituitary and leads to depletion of the readily releasable reserve of pituitary gonadotropins. Suppression of the elevated PRL level without correction of the hypothyroid state provides a practical method to test this hypothesis. In the adult, it has already been shown that hyperprolactinemia plays a primary etiologic role in the gonadal dysfunction. REFERENCES

1. Kendle FW: Case of precocious puberty in a female cretin, Br Med J 1:246, 1905.

Volume 92 Number 1

2. Costin G, Kershnar AK, Kogut MD, and Turkington RW: Prolactin activity in juvenile hypothyroidism and precocious puberty, Pediatrics 50:881, 1972. 3. Barnes ND, Hayles AB, and Ryan R J: Sexual maturation in juvenile hypothyroidism, Mayo Clin Proc 48:849, 1973. 4. Rakoff J, Vandenberg G,, Siler TM, and Yen SSC: An integrated direct functional test of the hypophysis, Am J Obstet Gynecol 119:358, 1974. 5. Tsai CC, and Yen SSC: The effect of ethinyl estradiol administration during early foll cular phase on tile gonadotropin levels and ovarian function, J Clin Endocrinol Metab 33:917, 1971. 6. Judd HL, and Yen SSC: Serum androstenedione and testosterone levels during the menstrual cycle, J Clin Endocrinol Metab 36:475, 1973. 7. Foley TP, Jacobs LS, Hoffman W, Daughaday WH, and Blizzard RM: Human prolactin and thryotropin concentrations in the serums of normal and hypopituitary children before and after the administration of Synthetic thyrotropin releasing hormone, J Clin Invest 51:2143, 1972. 8. Kaplan SL, Grumbach MM, Friesen HG, and Costom BH: Thyrotropin-releasing factor (TRF) effect on secretion of human pituitary prolactin and thyrotropin in children and in idiopathic hypopituitary dwarfism: further evidence for hypophysiotropic hormone deficiencies, J Clin Endocrinol Metab 35:825, 1972. 9. Reiter EO, Kaplan SL, Coute FA, and Grumbach MM: Responsivity of pituitary gonadotropes to luteinizing hormone-releasing factor in idiopathic precocious puberty, precocious thelarche, precocious adrenarche, and in patients treated with medroxyprogesterone acetate, Pediatr Res 9:111, 1975. 10. Siler-Khodr TM, Mroueh AM, Khodr GS, and Jaber R: Correlation of pituitary status and testicular function in oligo- and azoospermic men, Endocrinology 100:A-000, 1977. 11. Van Wyk J J, and Grumbach MM: Syndrome of precocious menstruation and galactorrhea in juvenile hypothyroidism: an example of hormonal Overlap in pituitary feedback, J PEDIATR 57:416, 1960. 12. Wood LC, Olichney M, Locke H, Crispell KR, Thornton WN, and Kiley JI: Syndrome of juvenile hypothyroidism associated with advanced sexual development, J Clin Endocrinol Metab 25:1289, 1965. 13. Mroueh A, and Siler-Khodr TM: Ovarian refractoriness to gonadotropins in cases of inappropriate lactation: restoration of ovarian function with Bromaryptine, Am J Obstet C,y0ecol 127:291, 1977.

Precocious puberty in hypothyroidism

59

14. Voogt JL, and Meites J: Effects of an implant of prolactin in median eminence of pseudopregnant rats on serum and pituitary LH,, FSH and prolactin, Endocrinology 88:286, 1971. 15. Voogt JL, Clemens JA, and Meites J: Stimulation of pituitary FSH release in immature female rats by prolactin implant in median eminence, Neuroendocrinology 4:157, 1969. 16. Clemens JA, Minaguchi H, Storey R, Voogt JL, and Meites J: Induction of precocious puberty in female rats by prolactin, Neuroendocrinology 4:150, 1969. 17. McNatty KP, Sawers RS, and McNeilly AS: A possible role for prolactin in control of steroid secretion by the human graafian follicle, Nature 250:653, 1974. 18. Fang VS, Refetoff S, and Rosenfield RL: Hypogonadism induced by a transplantable, prolactin producing tumor in male rats: hormonal and morphological studies, Endocrinology 95:99[, 1975. 19. Schulz KD, Geiger W, Del Pozo E, Lose KH, K0nzig H J, and Lancranjan I: The influence of the prolactil~ inhibitor brom0criptin (CB 154) on human luteal function in vivo, Arch Gynaekol 221:93, 1976. 20. Yen SSC, Vandenberg G, and Siler TM: Modulation of pituitary responsiveness to LRF by estrogen, J Clin Endocrinol Metab 39:170, 1974. 21. Ehara Y, Siler T, Vanderberg G, Sinha YN, and Yen SSC: Circulating prolactin levels during the menstrual cycle: episodic release and diurnal variation, Am J Obstet Gynecol 117:962, 1973. 22. Ehara Y, Yen SSC, and Slier TM: Serum prolactin levels during puberty, Am J Obstet Gynecol 121:995, 1975. 23. Yen SSC, and Vicic WJ: Serum follicle stimulating hormone levels in puberty, Am J Obstet Gynecol 105:134, 1969. 24. Yen SSC, Vicic W J, and Kearchner DV: Gonadotropin levels in puberty. I. Serum luteinizing hormone, J Clin Endocrinol Metab 29:382, I969. 25. Strauss JH, Yen SSC, Benirschke K, Greenhoot JH, Rafoff JS, and Siler TM: Hypothalamic hypopituitarism in an adolescent girl: Assessment by a direct functional test of the hypophysis, J Clin Endocrinol Metab 39:639, 1974. 26. Korth-Schutz S, Levine LS, and New MI: Serum androgens in normal pre-pubertal children and in children with precocious adrenarche, J Clin Endocrinol Metab 42:117, 1976.