Br Med J (Clin Res Ed): first published as 10.1136/bmj.286.6366.664 on 26 February 1983. Downloaded from

664 BRITISH MEDICAL JOURNAL VOLUME 286 26 FEBRUARY 1983 Plainly the patient will have to come to terms with the years. The first sign ofpuberty in boys is an increase in testicu- illness, and this may need the well timed help of a counsellor, lar size, which can be assessed volumetrically using an orchido- who may be a doctor, nurse, social worker, or psychiatrist, meter.2 Since this event is not outwardly obvious, girls are or even a close friend or relative. Regular support during the widely believed to develop earlier than boys. In fact, testicular treatment will help to minimise the distress caused by the enlargement starts on average at the age of 11 1 (range 10 to 14). side effects of the drugs. Antiemetics can usually control The pubertal growth spurt does, however, occur about two sickness, supplying an attractive wig in advance of alopecia years earlier in girls than in boys. Menarche is a late event in helps, and use of a "cold cap" may even prevent loss of hair. puberty: the mean age is 13, but the range is from 11 to 15. Sensible use of hypnotics can ensure a good night's sleep. The timing of these events in normal puberty needs to be Explanation that the problems are expected and that things taken into account in defining precocious or early puberty. are not going wrong may often relieve anxiety without the In general, development of the breast before 8 years or en- need for tranquillisers, but sometimes help is needed with largement of the testes before 9 years, followed in each case by severe depression. the progressive onset of other signs associated with normal Patients seem to cope with chemotherapy in the same way puberty, is regarded as true central precocious puberty. that they respond to other life events. Some take it in their The terminology used implies that the onset of puberty is due stride, others manage with difficulty, and some not at all. to premature activation of the hypothalamic-pituitary- Charting reactions and miseries seems an insensitive procedure gonadal axis.3 In contrast, puberty is termed pseudoprecocious and unlikely to improve the patient's lot, but indices of or false when the source of increased sex steroid secretion is performance status are of value as they are a constant reminder independent ofthis axis, as in autonomous adrenal and gonadal that a whole person is being treated and not just a disease or a tumours. The distinction is important when considering ap- blood count.6 The Karnofsky index, although 20 years old, propriate investigations. For example, a boy with early penile has stood the test of time and is often more useful than more and pubic hair growth but small testes has a peripheral source elaborate scores. ofexcess androgens such as congenital adrenal hyperplasia or an The emotional distress caused by cancer chemotherapy adrenal tumour. The signs ofpuberty in true central precocious must not be underestimated, but it is not difficult to under- puberty are usually isosexual or appropriate to the individual's stand. What is difficult is finding teams of experienced staff genotype. who can organise and supervise the treatments so that they Precocious puberty occurs about four to five times more can be completed without too much anxiety and distress and frequently in girls than in boys. Up to half the boys affected without patients "dropping out." Such teams need also to be have an organic cause-either tumours in the region of the prepared to evaluate new drugs and drug combinations for posterior hypothalamus, median eminence, and pineal gland effectiveness and for toxicity. The skill required indicates or the consequences ofprevious hydrocephalus, infection ofthe that such treatment should be undertaken only in specialised central nervous system, and occasionally trauma to the head. units. Intensive cancer chemotherapy is not suitable for Most girls with precocious puberty have no identifiable cause, occasional use by the inexperienced.@ though sometimes computed tomographic scanning may show DIANA BRINKLEY up small, probably benign, lesions in the supraseller region.4 Consultant Radiotherapist, These are often hamartomas. In the McCune-Albright syn- King's College Hospital, London SE5 9RS drome precocious puberty is associated with characteristic pigmentation ofthe skin and radiological changes ofpolyostotic http://www.bmj.com/ Shakespeare W. Hanmlet iv, iii, 9. fibrous dysplasia. Affecting mainly girls, the sequence of 2 Krumbhaar EB, Krumbhaar HD. The blood and bone marrow in yellow pubertal events is abnormal, with vaginal bleeding often cross gas (mustard gas) poisoning: changes produced in the bone marrow of fatal cases. Jfournal of Medical Research 1919;40:497-507. preceding breast development. A high incidence of non- Gilman A, Philips FS. Biological actions and therapeutic applications of specific abnormalities in the electroencephalogram has been 3-chloroethyl amines and sulfides. Science 1946;103:409-15. reported in children with Nerenz DR, Leventhal H, Love RR. Factors contributing to emotional idiopathic precocious puberty.5 distress during cancer chemotherapy. Cancer 1982;50:1020-7. Clinical examination should include detailed neurological Cohn KH. Chemotherapy from an insider's perspective. Lanlcet 1982;i:

and ophthalmological assessments. A radiograph is needed of on 27 September 2021 by guest. Protected copyright. 1006-9. Karnofsky DA. Meaningful clinical classification of therapeutic responses the skull, and ofthe hand and wrist for skeletal age, and a skele- to anticancer drugs. Clin Pharntacol Ther 1961 ;2:709-12. tal survey should be performed if the McCune-Albright Milsted RAV, Tattersall MHN, Fox RM, Woods RL. Cancer chemo- syndrome is suspected. A computed tomographic scan should therapy-what have we achieved? Lancet 1980;i :1343-6. also be done. Endocrine tests include an assessment of the gonadotrophin (luteinising hormone and follicle stimulating hormone) response to stimulation by gonadotrophin releasing hormone and measurement of the plasma concentration of oestradiol or testosterone. An undetectable serum concentration Precocious puberty and its of human chorionic gonadotrophin excludes a rare gonado- trophin producing tumour such as a hepatoblastoma or a management teratoma. Management is directed at treating the underlying cause, Puberty is probably one of the most turbulent ages of man, if that is appropriate, blocking the actions of gonadotrophins heralding the onset ofchange from childhood into adult life and and sex steroids, and, above all, providing suitable counselling the acquisition of reproductive ability. The process starts at a for emotional and behavioural problems. Neurosurgical treat- variable age and lasts three to four years. The physical signs ment of a lesion in the central nervous system is not warranted of puberty and the chronology of these events have been well solely on the basis of isolated signs of early puberty. In the documented by Tanner.' absence ofneurological signs a slow growing benign hamartoma In girls the earliest sign is enlargement of the breast bud, may be observed closely with serial computed tomographic occurring on average at the age of 11 with a range from 9 to 13 scans. Medical treatment may be given to decrease the Br Med J (Clin Res Ed): first published as 10.1136/bmj.286.6366.664 on 26 February 1983. Downloaded from BRITISH MEDICAL JOURNAL VOLUME 286 26 FEBRUARY 1983 665 production of gonadotrophins and sex steroids. Medroxypro- vided with expert psychological counselling during the critical gesterone is a synthetic progestin which inhibits secretion of years until the physical signs become quite acceptable within gonadotrophins by the pituitary. It may be given either as an the child's peer group. intramuscular depot preparation every two to four weeks or I A HUGHES (preferably) daily by mouth. The results in boys are disappoint- Senior Lecturer and Honorary Consultant Paediatrician, ing. Another progestational agent, cyproterone acetate, is more Welsh National School of Medicine, commonly used in Europe. In addition to its antigonadotrophic Cardiff CF4 4XN effects it has strong antiandrogenic properties.6 Both drugs Tanner JM. Grou-th at adolescence. 2nd ed. Oxford: Blackwell Scientific are effective in halting the progression of secondary sexual Publications, 1962. charactcristics and menses-and both have the side effect of 2 Zachmann M, Prader A, Kind HP, Hafliger H, Budliger H. Testicular volume during adolescence. Cross-sectional and longitudinal studies. suppressing adrenal secretion, but glucocorticoid supplemen- Helz Paediatr Acta 1974;29:61-72. tation is seldom necessary, except perhaps in extreme stress. Chaussain JL, Savage MO, Nahoul K, Brijawi A, Canlorbe P, Job JC. Other agents which have been tried in the treatment of Hypothalamo-pituitary-gonadal function in male central precocious preco- puberty. Clin Etndocrinol 1978;8:437-44. cious puberty include chlormadinone acetate and danazol.8 4Hung W, August GP, Brallier DR, Milhorat TH. Computerized tomo- None of these drugs affect the rapid growth and accelerated graphy in the evaluation of isosexual precocity. Anm 7 Dis Child 1980; 134:25-7. skeletal maturation characteristic of precocious puberty. Liu N, Grumbach MM, De Napoli RA, Morishima A. Prevalence of Children with precocious puberty are invariably tall at diagno- electroencephalographic abnormalities in idiopathic precocious puberty sis but become short adults. anid premature pubarche: bearing on pathogenesis and neuroendocrine regulation of puberty. 7 Clin Endocrinol Metab 1965;25:1296-308. Major advances have recently been made in the treatment of 6 Anonymous. Cyproterone acetate. Lancet 1976;i:1003-4. precocious puberty as a result of our increased knowledge of Stivel MS, Kauli R, Kaufman H, Laron Z. Adrenocortical function in children with precocious sexual development during treatment with the mechanisms of the onset of normal puberty.' 10 Studies in cyproterone acetate. Clin Endocrinol 1982;16 :163-9. rhesus monkeys and clinical observations in man have shown 8 Smith CS, Harris F. The role of danazol in the management of precocious that puberty is a reactivation ofrhythmic discharges ofgonado- puberty. Posrgrad Medy 1979;55, suppl 5:81-6. 9 Pohl CR, Knobil E. The role of the central nervous system in the control of trophin releasing hormone leading to pulsatile release of ovarian function in higher primates. Annu Rev Physiol 1982;44:583-93. gonadotrophins. During childhood this process lies dormant 10 Reiter EO, Grumbach MM. Neuroendocrine control mechanisms and the onset of puberty. Annu Rev Physiol 1982;44:595-613. because of a highly sensitive, sex steroid dependent hypothala- 1 Jakacki RI, Kelch RP, Sauder SE, Lloyd JS, Hopwood NJ, Marshall JC. mic-pituitary-gonadal negative feedback system. There is now Pulsatile secretion of luteinizing hormone in children. 7 Clin Endocrinol increasing evidence of pulsatile secretion of luteinising Mletab 1982 ;55 :453-8. 12 Leyendecker G, Wildt L, Hansmann M. Pregnancies following chronic hormone in prepubertal children. Puberty is characterised by intermittent (pulsatile) administration of Gn-RH by means of a portable an increase in amplitude of these pulses, occurring initially pump ("Zyklomat")-a new approach to the treatment of infertility in during sleep.'1 These physiological studies have found rapid hypothalamic amenorrhea. 7 Clin Endocrinol Metab 1980;51:1214-6. :3 Comite F, Cutler BG Jr, Rivier J, Vale WW, Loriaux DL, Crowley WF Jr. therapeutic application. Administration of gonadotrophin Short-term treatment of idiopathic precocious puberty with a long- releasing hormone in pulses to women with hypogonadotrophic acting analogue of luteinizing hormone-releasing hormone. N EnglJf Med has 1981 ;305:1546-50. hypogonadism and amenorrhoea restored menses, induced 14 Bergquist C, Nillius SJ, Wide L. Intranasal gonadotrophin-releasing ovulation, and later resulted in pregnancy.'2 If gonadotrophin hormone agonist as a contraceptive agent. Lancet 1979;ii:215-6, 7. releasing hormone is administered continuously pituitary secretion of gonadotrophins decreases, presumably because the gonadotrophes become refractory to further stimulation. Comite and her colleagues at the National Institutes of Health, http://www.bmj.com/ Bethesda, and Massachusetts General Hospital, Boston, have recently reported preliminary results from the use of a long A coordinated occupational acting gonadotrophin releasing hormone analogue in five girls with idiopathic central precocious puberty.13 Each patient re- health service in the NHS ceived the analogue by daily subcutaneous injection (4 iug,kg) for two months. The size of their breasts and the growth The National Health Service is the largest employer in

of their pubic hair decreased, and vaginal bleeding stopped. Europe, employing 1-5 million workers. Working in the NHS on 27 September 2021 by guest. Protected copyright. Basal and peak gonadotrophin concentrations before and after a cannot be described as dangerous compared with traditionally standard gonadotrophin releasing hormone stimulation test hazardous occupations, but workers are exposed to a wide were decreased during treatment. On stopping treatment range of circumstances and agents capable of causing ill hormone concentrations returned to pretreatment values within health, and over the years several calls have been made for eight weeks. In the short term this treatment appears most the establishment of an occupational health service.1-3 Why, effective. Whether it eventually has any substantial effect on then, have health authorities generally failed to provide a growth velocity and skeletal maturation is not yet known- service comparable to that in industry ? but the results are being awaited with keen interest. Some con- One important reason is that in the hospital service the cern has been expressed about the long term effects of this staff in the occupational health service are not the sole experts treatment, especially since an intranasal preparation of a on health. Hospital staff tend to assume that because their gonadotrophin releasing hormone agonist is being developed work is medical they have no need for an occupational health as a potential contraceptive agent.14 service. Doctors may treat members of the hospital staff for The treatment of the physical signs of precocious puberty is illnesses or injuries acquired at work, but unless specific steps relatively straightforward, but the associated psychological and are taken to collect the data the prevalence of ill health will behavioural disturbance demands a sensitive, understanding be underestimated. Moreover, treatment is only one aspect approach from the family, medical personnel, and teachers. of occupational health: other functions include the recognition Inevitably, most people's expectations ofemotional, social, and and control of hazards, health surveillance, rehabilitation, and educational maturity are influenced by the physical rather than advice to the management. the chronological age of the child. Families need to be pro- Probably the main reason for the little progress in establish-