Archives ofDisease in Childhood 1996;75:153-155 153

Male secondary to

panhypopituitarism Arch Dis Child: first published as 10.1136/adc.75.2.153 on 1 August 1996. Downloaded from

D P Burgner, S Kinmond, A M Wallace, D G Young, M G Forest, M D C Donaldson

Abstract oped than the right and a 1 x 0.6 cm was An infant with a 46XY karyotype was born easily palpated within it; a smaller gonad was with ambiguous genitalia, including mi- present within the right fold. The anus was crophallus and perineal . A normal and no other abnormalities were found gender was assigned due to ex- on examination. treme failure ofdevelopment ofthe exter- Rapid karyotyping from bone marrow aspi- nal genitalia. Subsequent investigations ration showed a 46XY complement, subse- demonstrated panhypopituitarism, and it quently confirmed on peripheral blood. A mic- is believed that severe gonadotrophin turating cystourethrogram showed a male type deficiency was responsible for the with a small utricle arising from below state. This case illustrates the need to the bladder neck. Pelvic ultrasound revealed evaluate the hypothalamic-pituitary axis normal renal and adrenal anatomy with no in selected cases of intersex, and also female structures. questions the prevailing assumption that On day 4 the baby fed poorly and blood glu- secretion during embryogen- cose fell to below 2 mmol/l, responding to esis is largely pituitary gonadotrophin intravenous dextrose. Serial plasma sodium independent, under the control of human and potassium values were normal, and renin chorionic gonadotrophin. activity was also normal for age. (Arch Dis Child 1996;75:153-155) Basal plasma cortisol levels (nmol/l) were consistently below 25 (normal > 50), rising to Keywords: ambiguous genitalia, panhypopituitarism. only 130 after 62.5 jg of intravenous Syn- acthen (expected rise > 200). An intravenous infusion of Synacthen (125 gg over 6 hours) Male produced a cortisol rise from < 25 to 375. pseudohermaphroditism can be defined Other plasma steroids (measured by radioim- as partial or complete failure of masculinisa- munoassay in Lyon, France, and given in tion in an individual with a 46XY karyotype. nmol/l with normal ranges for day 4 of life in The principal mechanisms are (a) abnormal parentheses) showed basal values as follows: testicular morphology resulting in a combina- http://adc.bmj.com/ tion of androgen and anti-Mullerian hormone progesterone 4.84 (0.7 to 6.5), andro- (AMH) deficiency so that poor masculinisa- tion is accompanied by persistence of female structures, (b) either specific biosynthetic Royal Hospital for Sick Children, Yorkhill, defects or androgen resistance where female Glasgow, University structures will be suppressed due to normal

Department of Child AMH secretion, and (c) Leydig cell unrespon- on September 28, 2021 by guest. Protected copyright. Health to D P Burgner siveness gonadotrophin stimulation. M D C Donaldson Secondary or tertiary deficiency of the hypothalamic pituitary gonadal axis is not gen- University erally listed as a recognised cause of male Department of Paediatric Surgery pseudohermaphroditism in endocrine refer- D G Young ence books.' 2 Indeed, gonadotrophin defi- ciency would not be expected to cause this Glasgow Royal problem if testosterone secretion fetal Infirmary, Glasgow, during Institute of life were largely under the control of placental Biochemistry human chorionic gonadotrophin (hCG) as is A M Wallace generally thought," or else under paracrine INSERM U329, control. Hopital Debrousse, We report a case in which male pseudoher- Lyon, France maphroditism was the initial manifestation in M G Forest evolving panhypopituitarism with severe gona- Ayrshire Central dotrophin deficiency. Hospital, Scotland, Department of Case report Paediatrics A term infant of non-consanguinous parents S Kinmond was noted to have ambiguous genitalia at birth. There was no relevant family history. On Correspondence to: Dr M D C Donaldson, Royal examination there was a 1.2 cm clitero-phallus, Hospital for Sick Children, with Yorkhill, Glasgow G3 8SJ. perineal hypospadias (fig 1). Figure 1 Perioperative photograph ofhEypopituitary The labioscrotal folds were fused with a 46XY infant showing ambiguous genitalia with Accepted 9 April 1996 median raphe. The left fold was more devel- microphallus andperineal hypospadias. 154 San Lazaro, Steele, Donaldson

stenedione 0.74 (0.5 to 2.8), 17 hydroxypro- mone deficiency together with severe gonado- gesterone 0.20 (1 to 6.8), dehydroepiandros- trophin and ACTH deficiency from birth.

terone (DHA) 6.11 (15 to 20) and its sulphate Although growth hormone was only just Arch Dis Child: first published as 10.1136/adc.75.2.153 on 1 August 1996. Downloaded from DHAS 59 (500 to 3500), and testosterone < subnormal at 9 months, the growth pattern 0.1 (0.85 to 1.45). and response to growth hormone therapy leave After intramuscular hCG 1500 units, the little doubt that the child is growth hormone testosterone rise was subnormal at 0.68 nmol/l, deficient, and it is likely that repeat GH stimu- with no rise in precursors. By contrast the lation testing would now show severe insuffi- 6-hour Synacthen infusion produced signifi- ciency consistent with an evolving pattern as cant rises in testosterone (2.74 nmol/l), proges- seen in optic nerve hypoplasia with hypopitui- terone (11.33 nmol/l), androstenedione (6.87 tarism (Donaldson M, unpublished observa- nmol/l), and 17 hydroxyprogesterone (47 tion). The low basal testosterone concentra- nmol/l), excluding a proximal enzyme defect of tions are consistent with severe gonadotrophin steroidogenesis such as P450 SCC. deficiency and the poor response to short hCG On day 11 it had been established that the stimulation test was presumably the result of child was a male pseudohermaphrodite with longstanding testicular understimulation. low testosterone levels, cortisol deficiency, The presence of morphologically normal extremely low DHA and DHAS (suggestive of and well differentiated albeit underdeveloped secondary adrenal insufficiency), and virtual testes with almost complete suppression of suppression of female structures, indicating Mullerian structures rules out the possibility of intact AMH production. A biochemical defect dysgenetic testes as the cause of defective mas- was therefore assumed but the cause was culinisation in this baby. Specific synthetic unclear. In view of the very poor phallic tissue enzyme defects were excluded by the plasma it was judged impossible to raise the child as a and urine steroid profiles before and after both male, even with hCG and testosterone therapy. hCG and Synacthen stimulation. A female gender was therefore assigned, A concurrent with hydrocortisone replacement started, and on panhypopituitarism is impossible to exclude day 18 the child underwent bilateral gonadec- but the likelihood ofboth conditions occurring tomy. Histology of testes showed immature in one individual must be extremely small. We hypoplastic testes with a reduced number of conclude therefore that the child's severe seminiferous tubules lined by spermatogonia failure to masculinise is likely to be related to and Sertoli cells, and stroma containing an the severe gonadotrophin deficiency. occasional cluster of small dense interstitial It has been generally accepted that testoster- cells and no tubular basement thickening. one secretion during embryogenesis is under At 3 months, stimulation with GnRH 100,g the control of placental hCG, and that and TRH 200 jg was carried out. FSH and LH pituitary gonadotrophins are only important in values were below 1 U/I throughout the test. later testosterone mediated aspects of male

TSH was 3.3 mU/l basally, with a rise to 46.8 development, such as growth of the external http://adc.bmj.com/ at 30 minutes and still 41.0 at 60 minutes. genitalia.4 In keeping with this view, Leydig Full pituitary function testing was per- cell proliferation correlates with peak placental formed at 8 months. LH and FSH remained hCG production at the end of the first trimes- consistently below lU/l after stimulation with ter4 while pituitary LH and FSH production GnRH. Basal T4 was low at 51 nmol/l, TSH peaks in the mid trimester, although their 2.2, 22.7, and 26.2 mU/l at 0, 30, and 60 min- secretion can be detected as early as five or six utes respectively following stimulation with weeks in pituitary cultures.' TRH, indicating hypothalamic hypothy- There are, however, objections to this model on September 28, 2021 by guest. Protected copyright. roidism. of fetal testosterone control. Differentiation of Following arginine infusion growth hor- the male genital tract is largely complete by mone peak was 19.8 mU/l at 60 minutes. By 12-13 weeks, yet hCG receptors are only 1 year of age supine length had fallen from the demonstrable in the human fetal testis by week 10th to the 3rd centile despite introduction of 12 of gestation.6 Moreover Word et al, working thyroxine treatment. Growth hormone was with in vitro fetal testis, found that hCG stimu- started at the age of 18 months and the child's lation had no significant effect on either height subsequently rose to the 50th centile. adenylate cyclase or testosterone production Currently the child is well and intellectually between 10 and 18 weeks gestation.7 normal. It has been shown previously that the Sertoli Computed tomography at 9 months showed cells exert a paracrine effect on the Leydig cells no abnormality of the hypothalamus or pitui- in the fetal testis and that this is under FSH tary and more definitive imaging with mag- control.8 Lecerf et al have recently confirmed netic resonance imaging is envisaged at a later an FSH induced Sertoli cell effect on fetal date. Ophthalmic review initially was sugges- Leydig cell function with stimulation of tive ofoptic nerve hypoplasia, but follow up has testosterone production in the fetal rat.9 We since shown 6/6 visual acuity unaided in both postulate that critical amounts of pituitary eyes. The mother has since given birth to a gonadotrophin are essential for normal pri- healthy girl and boy. mary sexual differentiation in the male fetus. Complete deficiency would thus explain the Discussion ambiguous genitalia seen in our child, and in There is no doubt about the diagnosis of pan- the 36 week male fetus with ambiguous genita- hypopituitarism in this case, with evolving lia and no detectable gonadotrophin secretion hypothalamic hypothyroidism and growth hor- reported by Siler-Khodr et al.' This model Outcome ofcriminal investigation into allegations ofsexual abuse 155

might also account for the case described by 3 Anderson DC. Physiology of human fetal sex differentia- tion. In: Brook CGD, ed. Clinical paediatric , Park et al where complete failure of masculini- 2nd Ed. Oxford: Blackwell, 1989:32-7.

sation was attributed to biological inactivity of 4 Saenger P. Abnormal sex differentiation. J Pediatr 1984; Arch Dis Child: first published as 10.1136/adc.75.2.153 on 1 August 1996. Downloaded from 104: 1-17. the gonadotrophin molecule.'0 We also specu- 5 Siler-Khodr TM, Morgenstern LL, Greenwood FC. late that in hypopituitary states such as Hormone synthesis and release from human fetal adeno- hypophysis in vitro. J Clin Endocrinol Metab 1974;39: anencephaly, in which the pituitary gland is 891-905. nearly always present, gonadotrophin secretion 6 Molsberry RL, Carr BR, Mendelson CR, Simpson ER. may be just sufficient to allow normal primary Human chorionic gonadotrophin binding in human fetal testes as a function of gestational age. J Clin Endocrinol sexual differentiation to occur, although subse- Metab 1982;55:791-4. quent genital growth is poor." 7 Word RA, George FW, Wilson JD, Carr BR. Testosterone synthesis and adenylate cyclase activity in the early human We suggest that severe pituitary gonado- fetal testis appear to be independent of human chorionic trophin deficiency should be more widely gonadotrophin control. J Clin Endocrinol Metab 1989; 69:204-8. recognised as a rare cause of male pseudoher- 8 Johnson BH, Ewing LL. Folllicle-stimulating hormone and maphroditism." In practical terms, we recom- the regulation oftestosterone secretion in rabbit testis. Sci- mend including gonadotrophin stimulation ence 1973;173:635-7. 9 Lecerf L, Rouiller-Fabre V, Levacher C, Gautier C, Saez testing in the workup of intersex cases where JM, Habert R. Stimulatory effect of follicle-stimulating basal gonadatrophins are low or undetectable. hormone on basal and luteinising hormone-stimulated testosterone secretions by the fetal rat testis in vitro. Endo- crinology 1993;133:2313-8. We thank Dr Martin Savage in London for his helpful 10 Park IJ, Burnett LS, Jones HW, Migeon CJ, Blizzard RM. A comments and criticisms of the manuscript. case of male pseudohermaphroditism associated with elevated LH, normal FSH and low testosterone possibly 1 Grumbach MM, Conte FA. Disorders ofsex differentiation. due to the secretion of an abnormal LH molecule. Acta In: Wilson JD, Foster DW, eds. Williams textbook of Endocrinol (Copenh) 1976;83: 173-81. endocrinology, 8th Ed. Philadelphia: WB Saunders, 11 Beam JG. Anencephaly and the development of the male 1992:853-951. genital tract. Acta Paediatr Hung 1968;9: 159-80. 2 Savage MO, Clinical aspects of intersex. In: Brook CGD, 12 Forest MG. Diagnosis and treatment of disorders of sexual ed. Clinical paediatric endocrinology, 2nd Ed. Oxford: development. In: De Groot U, ed. Endocrinology, 3rd Ed. Blackwell, 1989:38-54. Philadelphia: WB Saunders, 1995:1901-37. http://adc.bmj.com/ on September 28, 2021 by guest. Protected copyright.