Clinical Endocrinology ( 1979) 1 1 , 6 1 1-6 1 8
PRECOCIOUS PUBERTY ASSOCIATED WITH PRIMARY HYPOTHYROIDISM IN A MONGOL GIRL K . W . H A N C O C K , S. R . STITCH
AND
C. CHAPMAN
Department of Obstetrics and Cynaecology. Dillision ofsteroid Endocrinology. Department of Cheniical Pathology, Universitj,oflred.y and Department of Nuclear Medicine, The General Infirmary at b e d s (Rrceioed 16 Deceiiihrr 1978. rer iwd 14 M a ! , 1979. accepted30 M a y 1979)
SUMMARY
A mongo1 child suffering from hypothyroidism who presented with precocious puberty is described. A presumptive diagnosis of idiopathic precocious puberty was first made and she was treated initially with medroxyprogesterone acetate, and later with cyproterone acetate. The diagnosis of primary hypothyroidism was made late because of misleading results of protein bound iodine estimations. Subsequently, thyroid medication resulted in a prompt return to the normal range of the previously elevated levels of plasma gonadotrophins, thyroid stimulating hormone and plasma and urinary oestrogens, but the serum prolactin remained elevated for several months after therapy was begun. The association between precocious puberty and primary hypothyroidism is now a well recognized though uncommon entity (Costin el al., 1972; Brown et al., 1965). Moreover, Barnes et al. (1973) have drawn attention to the fact that in hypothyroid children sexual maturation is frequently in advance of somatic development though they may not exhibit frank precocious puberty. Until recently the mechanism underlying the advanced sexual development was obscure but evidence now suggests that in children thyrotrophin releasing hormone (TRH) may stimulate pituitary gonadotrophin secretion (Barnes et al. 1978). Case History The patient, a girl who exhibited trisomy-21, presented in October 1970 at the age of 4 years and 1 1 months (4”) with a six month history of recurrent vaginal bleeding. Her height and weight were below the third percentile for her age and skeletal maturity was assessed radiologically as 4 years and 6 months (Figs 1 and 2). There was moderate development of the breast areolae and nipples but no axillary or pubic hair. A palpable Correspondence Dr K W Hancock, Department of Obstetrics & Gynaecology, University of Leeds, Leeds LS2 9NG 0300-0664/79/1200-06I IS02 00
IQ
1979 Blackwell Scientific Publications
61 1
K. W . Hancock
612
el
al.
mass was found in the lower abdomen; X-ray of the skull revealed a normal pituitary fossa. METHODS FSH and LH: initial plasma assays were performed using a double-antibody radioimmunoassay. FSH antigen and antiserum were kindly supplied by Professor W.R. Butt, Birmingham and Midland Hospital for Women. LH antigen was obtained from Professor K.D. Bagshawe, New Charing Cross Hospital, London. The LH antiserum and precipitating antibody for these assays were products of Wellcorne Reagents Ltd., Beckenham, Kent. LEK 907, provided by the National Institutes of Health, was used as standard for both FSH and LH estimations. In the text the results have been expressed as i.u. per litre by converting the actual values obtained in ng LER 907,per ml on the basis of 20 i.u. per mg LER 907 for FSH and 60 i.u. per mg LER 907 for LH. Later plasma FSH, LH and TSH assays were carried out by a post-precipitated double-antibody radioimmunoassay using material supplied by the National Institutes of Arthritis, Metabolism and Digestive Diseases, National Pituitary Agency. Plasma oestradiol- 178 was measured by radioimmunoassay by the method of Eniment el ul. (1972). Plasma testosterone was measured by radioimmunoassay according to the method of Collins el al. (1972). Serum prolactin was determined by radioimmunoassay using antisera and antigen supplied by St. Bartholomew’s Hospital. Plasma thyroxine and
1
1
5
1
1
6
1
1
7
l
1
8
1
1
9
1
1
l
1
1 0 1 1
1
1
12
Aqe ( Y e a r s )
Fig. I . Patient’s body weight showing 3rd, 10th. 25th. SOth, 75th. 90th and 971h percentiles for age
Precocious puberrj, in Down's swdrorne
613
tri-iodothyronine were measured using a pre-precipitated double-antibody method. Urinary oestrone was measured by a modified method of Brown (unpublished). 17-0s and 17-OGS were assayed by a modification of the method of Metcalfe (1963). CLINICAL INVESTIGATIONS AND RESULTS On admission, protein bound iodine (375 nmol/l), urinary 17-oxosteroids (17-0s) (5 and 5 umo1/24 h) and 17-oxogenic steroids (17-OGS) (5 and 6 umolj24 h) were all within the normal range. Urinary oestrone excretion (9, 10 and 5 nmo1/34 h) was low. Gonadotrophin assays were not obtained. At examination under anaesthesia, curettage and laparoscopy were performed. The uterus was of adult size and some endometrium was obtained. The lower abdominal mass proved to be due to follicular cysts of the right ovary. The left ovary was similarly enlarged, but to a lesser degree. A diagnosis of idiopathic precocious puberty was made and treatment commenced with medroxyprogesterone acetate 50 mg daily by mouth. This controlled the vaginal bleeding. No further breast development occurred and the ovarian enlargement regressed but treatment was associated with excessive weight gain (Fig. 1 ) and an increase in height of 3.5 cm in the first year. Thereafter her height became static, well below the third percentile (Fig. 2 ) . During this period some pubic hair appeared. Reduction in the dosage of medroxyprogesterone acetate to 40 mg daily resulted in a recurrence of the vaginal bleeding. In December 1972, when she was aged 7 years and 1 month (7'), prior to changing the treatment to cyproterone acetate, X-rays of the pituitary fossa showed no abnormality, follicle stimulating hormone (FSH) levels were 11.0, 14.6 and 12.0 i.u. per litre (five to six
I
'3
'
, , /
L-Thvroaine
1
rd
percentile
/'
f
-... .........
/.
/*
/*
i
f
.i
i
N
5
6
7
8
9 1 0 1 1
12
Aqe ( Y e o r s )
Fig. 2. Patient's height showing 3rd percentile for age.
614
K. W . Hancock
el
al.
times normal adult values), luteinizing hormone (LH) levels were 1.9, 2.1 and 1.4 i.u. per litre (within the normal adult range), oestrone excretion was 71 nmol per 24 h (high and compatible with the follicular phase of the menstrual cycle), but plasma testosterone values remained low (0.7 nmol/l). Cyproterone acetate, 100 mg daily, controlled the vaginal bleeding, reduced the rate of weight gain and the growth of pubic hair. During this time serial assays of plasma gonadotrophins and oestradiol and urinary oestrone excretion showed no significant change (Fig. 3). Even the addition of ethinyl oestradiol 50 p g daily for 14 days to the cyproterone acetate therapy failed to suppress gonadotrophin secretion. Despite dieting she remained overweight and was listless and lethargic. Nine months after starting cyproterone acetate therapy, when 7 years and I0 months, she was admitted to hospital for a period of rigorous dieting. At this time the radiological bone age was reported as 5 years and 4 months; her protein bound iodine was 380 nmol/l. Significant weight loss was achieved by strict dieting. No changes occurred however, in the biochemical measurements. Whilst taking cyproterone acetate serial assays of urinary 1 7 - 0 s and I7-0CiS, plasma testosterone and liver function tests were performed. 1 7 - 0 s excretion varied between 7-18 pmol per 24 h while 17-OGS excretion was between 11-34 jimol per 24 h. These values were in the normal range for her age. Similarly her plasma testosterone
1 Ethinvl oestrodtoll IL-Thvroxlnel 18 16
\i
\
Age ( Y e a r s )
Fig. 3 . Plasma FSH, LH and oestradiol levels and urinary excretion o f oestrone prior to and during treatment with cyproterone acetate and following the institution of thyroid medication.
615
Precocious puberty in Down's syndronze
remained low at 0.7 nmol/l. Plasma oestradiol (5.5-16.6 nmol/l) and urinary oestrone excretion (71-83 nmo1/24 h) remained high throughout this period. The liver function tests were consistently normal during the 21 months treatment with cyprotetone acetate. When she was 8 years and 5 months a repeat protein bound iodine assay was reported at 80 nmol/l. Further investigations provided the results seen in Table 1. The diagnosis was therefore revised. Treatment was begun with I-thyroxine 0.05 mg mane; 0.025 mg nocte, resulting in a dramatic change in her condition. She became alert
Table I . Further investigations ~~~
Normal range Not detectable 6CL-140nmol/l Total thyroxine 1'6-3.2 Total triiodothyronine 0.15 nmol/l Binding index 08 1.2-1.8 Free thyroxine Not detectable 1.03-2.32 nmol/l Thyroid stimulating 200 kU/ml 10 20 hormone (TSH)
L-Thyroxine
0-0
. . 3 X
i
FSH
-4 LH
_J
20 /
15
8
A\
/
10
9
\
I1
Age (years)
Fig. 4. Plasma FSH. L H , TSH and serum prolactin levels prior to and following thyroid medication.
616
K . W . Hancock et al.
and active. Within 6 months she gained 3.5 cm in height and her skeletal maturation advanced to 7 years a n d 4 months. There has been n o further vaginal bleeding apart from one episode lasting 1 week, which commenced about 2 weeks after starting thyroid therapy. Slight breast development and the recurrence of pubic hair has been noted since March 1976, when she was 10 years and 4 months ( lo4). When last seen at 1 I years and 4 months this secondary sexual development was progressing normally. The results of serial assays of plasma FSH, LH, T S H and serum prolactin (PRL) a r e shown in Fig. 4. The assays for gonadotrophins used were changed and the normal ranges for adult females are FSH 3-10 i.u./litre and L H 10-25 i.u./litre. The upper limit of the normal range for serum prolactin is 500 mU/litre. In view of the normal results obtained from the initial protein bound iodine assays, thyroid binding globulin (TBG) was determined on samples of plasma obtained prior to and following the commencement of thyroid medication. Specimens obtained in April, August a n d September 1974 when she was 8s, g9 and 8'Oyears respectively showed levels of 23.8, 26.7 a n d 24.2 mg/litre. These values are normally only seen in pregnancy and in individuals with inherited high TBG. Specimens taken 10 and 14 months after starting I-thyroxine gave normal values of 10 and 11.8 nig/litre. DISCUSSION
If the results of the two initial protein bound iodine assays are accepted as accurately reflecting the patient's thyroid status, it would appear that she developed primary hypothyroidism 4 years after presenting with precocious puberty. In retrospect, however, the growth velocity illustrated in Fig. 2, together with the retarded bone age are so atypical of idiopathic precocious puberty, that it is virtually certain that hypothyroidism co-existed from the outset. T h e prompt remission of the abnormal gonadotrophin secretion following thyroxine therapy would also imply that this was the case. The elevation of her T B G levels was presumably due to her elevated plasma oestrogens and both fell on starting thyroid replacement therapy. Similar elevation of the TBG occurs in euthyroid individuals during pregnancy and results in raised serum levels of PBI and thyroxine. In this patient the indications are that she was suffering from hypothyroidism from a n early age and the increased levels of T B G are unlikely to have been responsible for the normal PBI levels observed. Since PBI estimations are particularly prone t o interfering reactions (Acland, 1971) we now feel that these initial measurements were erroneous. The results of the gonadotrophin assays indicate that the pituitary gonadotrophes responded to stimulation in a prepubertal manner, FSH production being in excess of that of LH, a s is also evident in the series of Barnes el NI.(1973). In the hypothyroid state the hypothalamic-pituitary axis was remarkably unresponsive t o gonadal steroid suppression: even the administration of 50 ug ethinyl oestradiol daily for 14 days failed to reduce gonadotrophin levels. The precise mechanism underlying the syndrome has remained obscure until recently, when Barnes et uf. (1978) demonstrated that thyrotrophin releasing hormone ( T R H ) stimulates release of F S H but not L H in both normal and hypothyroid children. Thus the elevated gonadotrophin secretion which predominantly involves FSH a n d the hyperprolactinaemia which was present in this case and the two children described by Costin e l (if. (1972) may be due to increased T R H secretion. However, in a study of children with
Precocious puberty in Dowrr 's syridroine
617
growth hormone and TSH deficiency, in whom the latter was due to lack ofTRH, Foley et al. ( 1972) observed hyperprolactinaemia which resolved following thyroid replacement therapy. I t therefore appears that hyperprolactinaemia associated with congenital hypothyroidism may be due to factors other than, or in addition to, increased TRH secretion. The sustained hyperprolactinaemia which persisted for several months following the institution of thyroid therapy, despite the prompt fall in FSH, LH and TSH, has been attributed to hyperplasia of the lactotrophes consequent upon prolonged TRH stimulation (Costin el al. 1972). The combination of hyperprolactinaemia and precocious ovarian activity would appear somewhat paradoxical in view of the evidence that prolactin reduces the sensitivity of the ovaries to gonadotrophin stimulation (McNatty, 1974; Besser & Thorner, 1976). Perhaps the relatively infrequent association between hypothyroidism and frank precocious puberty is attributable to a prolactin induced block on gonadal response, which is only overcome when FSH secretion is grossly elevated, as occurred in the present case. The occurrence of ovarian enlargement due to follicular cysts is well recognized in precocious puberty and Raiti ( 1 970) has emphasized the importance of avoiding surgical resection of such cysts because of the risk of subsequent premature gonadal failure. The involution of the cysts on medroxyprogesterone therapy and continued suppression during cyproterone acetate treatment presumably resulted from the blocking of gonadotrophin receptors on the ovarian tissue since the abnormal gonadotrophin levels were maintained .
AC K N O W LE DG E M E N T S
We are grateful to Mr. R. Mansfield, F.I.M.L.T.,Department of Biochemical Endocrinology, Chelsea Hospital for Women, for carrying out plasma gonadotrophin oestrogen and testosterone assays, and to Dr. W.A. Burr, Department of Medicine, University of Birmingham, who performed the plasma thyroid binding globulin assays. Schering Chemicals Ltd., Burgess Hill, Sussex, kindly supplied the cyproterone acetate and arranged for the initial assays to be performed.
R 1; F E R E N C E S ACLAND, J.D. (1971) The interpretation of the serum protein-bound iodine: a review. Journal of Clitlicul Parhology,24, 187-2 18. BARNES, N.D., HAYLES, A.B. & RYAN, R.J. (1973) Sexual maturation in juvenile hypothyroidism. MUJ,O Clinic Proceedings. 48,849-856. BARNES, N.D., JONES, J . & GRANT, D.B. (1978) T R H releases FSH in children. an explanation for the elevated FSH levels in juvenile hypothyroidism. Pardiarrrc Re.reur[A. 12, 155 (Abstr.). BESSER, G . M . & THORNER, M.O. (1976) Broinocriptine in the treatment ofthe hyperprolactinaemia-hypogonadism syndrome. Postgrarfuafe Medical Journal. 52, (Suppl. I ) , 64-70. BROWN, D.M., JENNESS, R. & ULSTROM. R.A. (1965) A study of the composition of milk from a patient with hypothyroidism and galactorrhoed. JoitrriulofCIinrrlrl Et~docrittolog~~ and Mefoholrsm. 25, 1225.-1230 COLLINS, W.P.. MANSFIELD, M.D., ALLADINA. N.S & SOMMERVILLE I.F. (1972) Radioimmunoassay of plasma testosterone. Journal of Sferoid Biochemisfry. 3, 333- 348. COSTIN, G., KERSHNAR, A.K., KOGUT, M.D. & TTIJRKINGTON, R.W. (1972) Prolactin activity in juvenile hypothyroidism and precocious puberty. Puediurric.T. 50.88 1-889.
618
K . W. Hancock el al.
EMMENT, Y . , COLLINS, W.P. & SOMMERVILLE, I.F. (1972) Radioimmunoassay of oestrone and oestradiol in human plasma. Acra Endocrinologica, (Khh) , 69,567-582. FOLEY, T.P.Jr., JACOBS, L.S., HOFFMAN, W., D A U G H A D A Y , W . H . & BLIZZARD, R.M (1972) Human prolactin and thyrotrophin concentrations in the serum of normal and hypopituitary children before and after the administration of synthetic thyrotrophin-releasing hormone. Journal (J/ Clrnicul /ncwriga/ion.51, 2143-2150. MCNATTY, K.P.. SAWERS, R.S. & MCNEILLY, A S . (1974) A possible role for prolactin in control of steroid secretion by the human Graafian follicle. Narure, 250,653-655. METCALFE. M . G . (1963) A rapid method for measuring 17-hydroxycorticoste:oidsin urine. Journal q/ Endocrinology. 2 6 , 4 1 5 4 2 3 . RAITI, S . ( 1970) Precocious Puberty. Bri/ish Journal of Hospiral Medic.iw. 4,873-878.
PRECOCIOUS PUBERTY ASSOCIATED WITH PRIMARY HYPOTHYROIDISM IN A MONGOL GIRL K . W . H A N C O C K , S. R . STITCH
AND
C. CHAPMAN
Department of Obstetrics and Cynaecology. Dillision ofsteroid Endocrinology. Department of Cheniical Pathology, Universitj,oflred.y and Department of Nuclear Medicine, The General Infirmary at b e d s (Rrceioed 16 Deceiiihrr 1978. rer iwd 14 M a ! , 1979. accepted30 M a y 1979)
SUMMARY
A mongo1 child suffering from hypothyroidism who presented with precocious puberty is described. A presumptive diagnosis of idiopathic precocious puberty was first made and she was treated initially with medroxyprogesterone acetate, and later with cyproterone acetate. The diagnosis of primary hypothyroidism was made late because of misleading results of protein bound iodine estimations. Subsequently, thyroid medication resulted in a prompt return to the normal range of the previously elevated levels of plasma gonadotrophins, thyroid stimulating hormone and plasma and urinary oestrogens, but the serum prolactin remained elevated for several months after therapy was begun. The association between precocious puberty and primary hypothyroidism is now a well recognized though uncommon entity (Costin el al., 1972; Brown et al., 1965). Moreover, Barnes et al. (1973) have drawn attention to the fact that in hypothyroid children sexual maturation is frequently in advance of somatic development though they may not exhibit frank precocious puberty. Until recently the mechanism underlying the advanced sexual development was obscure but evidence now suggests that in children thyrotrophin releasing hormone (TRH) may stimulate pituitary gonadotrophin secretion (Barnes et al. 1978). Case History The patient, a girl who exhibited trisomy-21, presented in October 1970 at the age of 4 years and 1 1 months (4”) with a six month history of recurrent vaginal bleeding. Her height and weight were below the third percentile for her age and skeletal maturity was assessed radiologically as 4 years and 6 months (Figs 1 and 2). There was moderate development of the breast areolae and nipples but no axillary or pubic hair. A palpable Correspondence Dr K W Hancock, Department of Obstetrics & Gynaecology, University of Leeds, Leeds LS2 9NG 0300-0664/79/1200-06I IS02 00
IQ
1979 Blackwell Scientific Publications
61 1
K. W . Hancock
612
el
al.
mass was found in the lower abdomen; X-ray of the skull revealed a normal pituitary fossa. METHODS FSH and LH: initial plasma assays were performed using a double-antibody radioimmunoassay. FSH antigen and antiserum were kindly supplied by Professor W.R. Butt, Birmingham and Midland Hospital for Women. LH antigen was obtained from Professor K.D. Bagshawe, New Charing Cross Hospital, London. The LH antiserum and precipitating antibody for these assays were products of Wellcorne Reagents Ltd., Beckenham, Kent. LEK 907, provided by the National Institutes of Health, was used as standard for both FSH and LH estimations. In the text the results have been expressed as i.u. per litre by converting the actual values obtained in ng LER 907,per ml on the basis of 20 i.u. per mg LER 907 for FSH and 60 i.u. per mg LER 907 for LH. Later plasma FSH, LH and TSH assays were carried out by a post-precipitated double-antibody radioimmunoassay using material supplied by the National Institutes of Arthritis, Metabolism and Digestive Diseases, National Pituitary Agency. Plasma oestradiol- 178 was measured by radioimmunoassay by the method of Eniment el ul. (1972). Plasma testosterone was measured by radioimmunoassay according to the method of Collins el al. (1972). Serum prolactin was determined by radioimmunoassay using antisera and antigen supplied by St. Bartholomew’s Hospital. Plasma thyroxine and
1
1
5
1
1
6
1
1
7
l
1
8
1
1
9
1
1
l
1
1 0 1 1
1
1
12
Aqe ( Y e a r s )
Fig. I . Patient’s body weight showing 3rd, 10th. 25th. SOth, 75th. 90th and 971h percentiles for age
Precocious puberrj, in Down's swdrorne
613
tri-iodothyronine were measured using a pre-precipitated double-antibody method. Urinary oestrone was measured by a modified method of Brown (unpublished). 17-0s and 17-OGS were assayed by a modification of the method of Metcalfe (1963). CLINICAL INVESTIGATIONS AND RESULTS On admission, protein bound iodine (375 nmol/l), urinary 17-oxosteroids (17-0s) (5 and 5 umo1/24 h) and 17-oxogenic steroids (17-OGS) (5 and 6 umolj24 h) were all within the normal range. Urinary oestrone excretion (9, 10 and 5 nmo1/34 h) was low. Gonadotrophin assays were not obtained. At examination under anaesthesia, curettage and laparoscopy were performed. The uterus was of adult size and some endometrium was obtained. The lower abdominal mass proved to be due to follicular cysts of the right ovary. The left ovary was similarly enlarged, but to a lesser degree. A diagnosis of idiopathic precocious puberty was made and treatment commenced with medroxyprogesterone acetate 50 mg daily by mouth. This controlled the vaginal bleeding. No further breast development occurred and the ovarian enlargement regressed but treatment was associated with excessive weight gain (Fig. 1 ) and an increase in height of 3.5 cm in the first year. Thereafter her height became static, well below the third percentile (Fig. 2 ) . During this period some pubic hair appeared. Reduction in the dosage of medroxyprogesterone acetate to 40 mg daily resulted in a recurrence of the vaginal bleeding. In December 1972, when she was aged 7 years and 1 month (7'), prior to changing the treatment to cyproterone acetate, X-rays of the pituitary fossa showed no abnormality, follicle stimulating hormone (FSH) levels were 11.0, 14.6 and 12.0 i.u. per litre (five to six
I
'3
'
, , /
L-Thvroaine
1
rd
percentile
/'
f
-... .........
/.
/*
/*
i
f
.i
i
N
5
6
7
8
9 1 0 1 1
12
Aqe ( Y e o r s )
Fig. 2. Patient's height showing 3rd percentile for age.
614
K. W . Hancock
el
al.
times normal adult values), luteinizing hormone (LH) levels were 1.9, 2.1 and 1.4 i.u. per litre (within the normal adult range), oestrone excretion was 71 nmol per 24 h (high and compatible with the follicular phase of the menstrual cycle), but plasma testosterone values remained low (0.7 nmol/l). Cyproterone acetate, 100 mg daily, controlled the vaginal bleeding, reduced the rate of weight gain and the growth of pubic hair. During this time serial assays of plasma gonadotrophins and oestradiol and urinary oestrone excretion showed no significant change (Fig. 3). Even the addition of ethinyl oestradiol 50 p g daily for 14 days to the cyproterone acetate therapy failed to suppress gonadotrophin secretion. Despite dieting she remained overweight and was listless and lethargic. Nine months after starting cyproterone acetate therapy, when 7 years and I0 months, she was admitted to hospital for a period of rigorous dieting. At this time the radiological bone age was reported as 5 years and 4 months; her protein bound iodine was 380 nmol/l. Significant weight loss was achieved by strict dieting. No changes occurred however, in the biochemical measurements. Whilst taking cyproterone acetate serial assays of urinary 1 7 - 0 s and I7-0CiS, plasma testosterone and liver function tests were performed. 1 7 - 0 s excretion varied between 7-18 pmol per 24 h while 17-OGS excretion was between 11-34 jimol per 24 h. These values were in the normal range for her age. Similarly her plasma testosterone
1 Ethinvl oestrodtoll IL-Thvroxlnel 18 16
\i
\
Age ( Y e a r s )
Fig. 3 . Plasma FSH, LH and oestradiol levels and urinary excretion o f oestrone prior to and during treatment with cyproterone acetate and following the institution of thyroid medication.
615
Precocious puberty in Down's syndronze
remained low at 0.7 nmol/l. Plasma oestradiol (5.5-16.6 nmol/l) and urinary oestrone excretion (71-83 nmo1/24 h) remained high throughout this period. The liver function tests were consistently normal during the 21 months treatment with cyprotetone acetate. When she was 8 years and 5 months a repeat protein bound iodine assay was reported at 80 nmol/l. Further investigations provided the results seen in Table 1. The diagnosis was therefore revised. Treatment was begun with I-thyroxine 0.05 mg mane; 0.025 mg nocte, resulting in a dramatic change in her condition. She became alert
Table I . Further investigations ~~~
Normal range Not detectable 6CL-140nmol/l Total thyroxine 1'6-3.2 Total triiodothyronine 0.15 nmol/l Binding index 08 1.2-1.8 Free thyroxine Not detectable 1.03-2.32 nmol/l Thyroid stimulating 200 kU/ml 10 20 hormone (TSH)
L-Thyroxine
0-0
. . 3 X
i
FSH
-4 LH
_J
20 /
15
8
A\
/
10
9
\
I1
Age (years)
Fig. 4. Plasma FSH. L H , TSH and serum prolactin levels prior to and following thyroid medication.
616
K . W . Hancock et al.
and active. Within 6 months she gained 3.5 cm in height and her skeletal maturation advanced to 7 years a n d 4 months. There has been n o further vaginal bleeding apart from one episode lasting 1 week, which commenced about 2 weeks after starting thyroid therapy. Slight breast development and the recurrence of pubic hair has been noted since March 1976, when she was 10 years and 4 months ( lo4). When last seen at 1 I years and 4 months this secondary sexual development was progressing normally. The results of serial assays of plasma FSH, LH, T S H and serum prolactin (PRL) a r e shown in Fig. 4. The assays for gonadotrophins used were changed and the normal ranges for adult females are FSH 3-10 i.u./litre and L H 10-25 i.u./litre. The upper limit of the normal range for serum prolactin is 500 mU/litre. In view of the normal results obtained from the initial protein bound iodine assays, thyroid binding globulin (TBG) was determined on samples of plasma obtained prior to and following the commencement of thyroid medication. Specimens obtained in April, August a n d September 1974 when she was 8s, g9 and 8'Oyears respectively showed levels of 23.8, 26.7 a n d 24.2 mg/litre. These values are normally only seen in pregnancy and in individuals with inherited high TBG. Specimens taken 10 and 14 months after starting I-thyroxine gave normal values of 10 and 11.8 nig/litre. DISCUSSION
If the results of the two initial protein bound iodine assays are accepted as accurately reflecting the patient's thyroid status, it would appear that she developed primary hypothyroidism 4 years after presenting with precocious puberty. In retrospect, however, the growth velocity illustrated in Fig. 2, together with the retarded bone age are so atypical of idiopathic precocious puberty, that it is virtually certain that hypothyroidism co-existed from the outset. T h e prompt remission of the abnormal gonadotrophin secretion following thyroxine therapy would also imply that this was the case. The elevation of her T B G levels was presumably due to her elevated plasma oestrogens and both fell on starting thyroid replacement therapy. Similar elevation of the TBG occurs in euthyroid individuals during pregnancy and results in raised serum levels of PBI and thyroxine. In this patient the indications are that she was suffering from hypothyroidism from a n early age and the increased levels of T B G are unlikely to have been responsible for the normal PBI levels observed. Since PBI estimations are particularly prone t o interfering reactions (Acland, 1971) we now feel that these initial measurements were erroneous. The results of the gonadotrophin assays indicate that the pituitary gonadotrophes responded to stimulation in a prepubertal manner, FSH production being in excess of that of LH, a s is also evident in the series of Barnes el NI.(1973). In the hypothyroid state the hypothalamic-pituitary axis was remarkably unresponsive t o gonadal steroid suppression: even the administration of 50 ug ethinyl oestradiol daily for 14 days failed to reduce gonadotrophin levels. The precise mechanism underlying the syndrome has remained obscure until recently, when Barnes et uf. (1978) demonstrated that thyrotrophin releasing hormone ( T R H ) stimulates release of F S H but not L H in both normal and hypothyroid children. Thus the elevated gonadotrophin secretion which predominantly involves FSH a n d the hyperprolactinaemia which was present in this case and the two children described by Costin e l (if. (1972) may be due to increased T R H secretion. However, in a study of children with
Precocious puberty in Dowrr 's syridroine
617
growth hormone and TSH deficiency, in whom the latter was due to lack ofTRH, Foley et al. ( 1972) observed hyperprolactinaemia which resolved following thyroid replacement therapy. I t therefore appears that hyperprolactinaemia associated with congenital hypothyroidism may be due to factors other than, or in addition to, increased TRH secretion. The sustained hyperprolactinaemia which persisted for several months following the institution of thyroid therapy, despite the prompt fall in FSH, LH and TSH, has been attributed to hyperplasia of the lactotrophes consequent upon prolonged TRH stimulation (Costin el al. 1972). The combination of hyperprolactinaemia and precocious ovarian activity would appear somewhat paradoxical in view of the evidence that prolactin reduces the sensitivity of the ovaries to gonadotrophin stimulation (McNatty, 1974; Besser & Thorner, 1976). Perhaps the relatively infrequent association between hypothyroidism and frank precocious puberty is attributable to a prolactin induced block on gonadal response, which is only overcome when FSH secretion is grossly elevated, as occurred in the present case. The occurrence of ovarian enlargement due to follicular cysts is well recognized in precocious puberty and Raiti ( 1 970) has emphasized the importance of avoiding surgical resection of such cysts because of the risk of subsequent premature gonadal failure. The involution of the cysts on medroxyprogesterone therapy and continued suppression during cyproterone acetate treatment presumably resulted from the blocking of gonadotrophin receptors on the ovarian tissue since the abnormal gonadotrophin levels were maintained .
AC K N O W LE DG E M E N T S
We are grateful to Mr. R. Mansfield, F.I.M.L.T.,Department of Biochemical Endocrinology, Chelsea Hospital for Women, for carrying out plasma gonadotrophin oestrogen and testosterone assays, and to Dr. W.A. Burr, Department of Medicine, University of Birmingham, who performed the plasma thyroid binding globulin assays. Schering Chemicals Ltd., Burgess Hill, Sussex, kindly supplied the cyproterone acetate and arranged for the initial assays to be performed.
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