29 32 E. /oW.LET-, Ph. BRlMLLE , P. CARAYON, Th. oo::ASTELLE 28 (Int r. by M.C. Postel-Vinay). Thyroid dysfunction in pseudohypoparathyroidism : evidence for a coupling failure of the thyrotropin receptor adenylate cyclase system asso- ciated with morphological abnormalities of the thyroid follicles. de Pediatrie, HOpital Ch. Nicol le, 76031 RDUEN, FRANCE A case of pseudohypoparathyroid ism type I in a 17 years old fe- male coexisting w ith thyroid dysfunction meeting all the criteria for thyrotropin ( TSH) insensitivity is studied. Thyroid gland was not enlarged as confinned by sc int iscan. Labora- tory findings included: high basal concentration of TSH (17-19.2 ).lU/ml), normal values of circulating thyroid honnones (T4 : 6.3 pg/ml, T3 : 98 ng/ml) exagerated response of TSH to thyrotropin re- leasing hormone (TRH) (200)Jg) and low 131 I thyroid uptake with impaired response to exogenous TSH (bovine TSH 10 UI daily for 6 days). After T3 therapy (SO)Jg per day for 2 months ), serum TSH de- creased to the normal range and its response to TRH almost normal i- ze. Tests for ci rculating thyroid antibodies were negative. Light microscopy of a biopsy specimen showed a heterogenous cellular ac- t ivity with large follicles w ith abundant colloid and flattened li- ning cells. The electron microscopy showed deep infoldings of the basal ment>rane. The TSH receptor as well as the basal and NaF sti - mulated aden ylate cyclase (AC) of thyroid membranes were found to be normal, but the ability of TSH to stimulate AC was markedly de- creased suggesting a coupling abnormality between the TSH receptor and AC. This abnormality could cause the res istance of target or- gans in pseudohypoparathyroid ism to parathyroid hormone. F. BIDLINGMAIER and D. KNORR, Children's Hospital, University of Munich, Germany. Development of the negative feedback control system of the hypothalamo-pituitary-gonadal (HPG) axis in the male rat fetus. To evaluate the development of the HPG axis the me- thod of immunologic hormone inactivation was used to study male rat fetuses at different ages of gestation . From the 12th day of gestation pregnant rats were pas- sively immunized against testosterone (T) by daily in- jections of rabbit antiserum with high binding capaci- ty for T. Fetuses were studied on each day of gesta- tion starting at day 18. Antibodies against T were de- tected in all fetal plasma samples. While the reduc- tion of circulating free T by antibody binding did not affect the differentiation of the male genital tract it markedly stimulated the endocrine activity of the testes. At day 19 and all subsequent days of gestation the test icular T content -an index of circulating go- nadotropins- was significantly higher in immunized fe- tuses than in controls. However, this difference was not yet apparent at day 18 when the normal fetal rat testis shows its peak activity. These results indicate that in the male rat fetus the negative feedback be- tween gonads and hypothalamo-pituitary system develops between day 18 and 19 of gestation when the differen- tiation of the genital tract is already well advanced. S.J . Clark*, D.M. Styne, S.L . Kaplan and M .M. Grumbach 30 Department of Pediatrics, University of California San Francisco, San Francisco, CA. Down-regulation of gonadotropin release by the ovine fetal pitui- tary gland by the superagonist D-Tr p6Pr 09NET-LRF . D-Trp6Pr09NET-LRF (Trp6-LRF) a super agonist analogue of LRF has caused suppression of gonadotropin secretion when administered chronically in animals and in humans , but has not been studied in the fetus. In 3c hronically catheterized ovine fetuses ages lOS- 130 days (term l47t3), spontaneous LH pulses of 3-8 ng/mI occurred every 3-4 hrs with baseline levels of less than 1 ng/ml. FSH levels ranged from 4-8 nglml and did not vary with the LH discharge. Ad- ministration of S synthetic LRF IV produced a mean incremental increase (6) of LH of 6.8 nglml (range 5.8-7.7 ng/mI) , while the mean 6 of FSH was 1.9 nglml (0.9-2 .9 ng/ml). After the first 10 dose of Trp6-LRF IV, the mean 6 of LH was 16.4 nglml (4.9-25.6 ngl ml), and the mean 6 of FSH was 3.9 ng/ml (2.9-4.7 ng/ml) . Elevated levels of LH and FSH were sustained for 2 hrs after the agoniat. A second 10 dose gi ven 24 hrs later did not induce a significant rise in LH or FSH . Intravenoua LRF elicited a minimal riae in LH and FSH during a 2-14 day study period, without measurable LH pul- ses. The findings are consistent with an initial phase in which Trp6-LRF stimulates FSH and LH release followed by s prolonged phase of refractoriness to either LRF or the LRF agonist. The later effect is consistent with down-regulation of fetal pituitary LRF receptors. These observations provide further support for the in- fluence of endogenous fetal LRF on fetal gonadotropin secretion and of neuroendocrine control mediated by LRF 8S early as 105 days of gestation. 31 o.c. Green, R. Sllkiss: M.Seron-Ferre"'nd R.B. Jaffe* Northwestern University , Chicago, and U. of calif- ornU , san Francisco, U.S.A. Human Fetal Adrenal Cell Responses to ACTH and Pituitary Extracts. Human fetal adrenal tissues were studied in dispersed cell susp- ensions prepared by collagenase digestion:triplicate aliquots were incubated for 2 hours : control cells were compared to cells stim- ulated with 3 dilutions of ACTH and compared to responses from cells stimulated with 3 dllutlons of 2 fract ions prepared from hutDlln pituitaries ("A" and IIBU) . Crude fraction A contained FSH, LH and TSH; B contained ACTH, MSH and other peptides. 4 specimens with single adrenal weights of 128 mg, 243 mg, 488 mg and 9lS mg were studied. Incubation medium was analyzed for dehydroepiandro- sterone sulfate (DHAS) and corticoids (C). Unstimulated C secret- ion was similar in all weights (137 + 63 pglmlllOO ,OOO cells) ; DHAS secretion was varUble but incr.ased with increasing siEe (16 nglml to 56 nglmlllOO,OOO cells) . ACTH caused dose-relate o proportlonate increases in both DHAS and C in all; plt. frx "A" gave greater DHAS responaes than ACTH in the 243 mg adrenal: DHAS:C ratio of 233:1 for ACTH and 7051:1 for However, this was not found in the more mature 915 mg gland (311:1 for ACTH and 191:1 for "A"). "B" reacted like ACTH. We conclude that (a) the developing fetal adrenal shows changing responses to different stimuli , perhaps reflecting changes in receptor response, number or discrimination, and (b) pltuitary extrsct may contain an androgen stimulator effective at varUble stages of development. J .W. REYNOLDS AND C.V. CARLSON* Dept of Pediatrics , Univ of Oregon Health Sciences Center, Portland , OR, USA. Fetoplacental Steroid Metabolism in Prolonged Pregnancy and Post- maturity Syndrome . Previoua work from this laborat ory (Pediat . Res. 14:1367 , 1990) showed that post-term infants ( >42 wk. gest ation) with postmaturi- ty syndrome had normal umbilical venous dehydroepiandrosterone sulfate (DHAS) levels, but low unconjugated estriol (E) l evels , as compared to post-term infants with no evidence of dysmaturity. To investigate further whether placental conversion of neutral steroids to estrogens is more limiting for E 3 production than fe- tal adrenal DHAS secretion, we studied 14 women with prolonged prognancy ( >42 wk) and 9 control 39-41 wk gestation women by SO mg I.V. DHAS infusions 1-3 days before delivery . The DHAS was lon- ger in post-term pregnanc ies than in controls (3.46 + 1.13 hr vs . 2.79 ± LOS hr. p <0.01) , and the estrone (E l) increases at 2 and 3 hr ., and estradiol-17B (E 2) increases at 2 and 4 hr. ( p <O. OS) were less in post-term than control pregnancies. These findi ngs indicate diminished placental aromatizing function in pr olonged pregnancy. However, no differences between pregnancies with and without post-mature fetuses could be found . In contrast, R i , E 2 and DHAS levels in umbilicsl venous blood levels were simi ar, and E levels were lower (p <0.05), in postmature newborns when compar- ed to controls . These cord blood values indicate that fetal hepat- ic l6a-hydroxylase may be the limiting ste p in fetoplacental E 3 production in some postmature fetuses. 33 J.D. BAILEY, M. KAUFMAN. and L. PINSKY*, Univer sity of Toronto, The Hospital for Sick Children , Toronto and Lady Davis Institute for Medical Rese arch, Montreal, Canada. Defective up-regulation of androgen-receptor activity: a new marker of androgen resistance (AR) in man. An infant ( #99) with ambiguous genitali a was investigated for androgen resistance. Foreskin-derived fibroblasts were normal in respect of : Sa-reductase activit y (23 pmol/mg protein/hr); re - ceptor concentration (2S fmol/mg protein); dissociation constant oM); dissociation rase (k-1-6xlO- 3min-1 )of the whgle cel l DHT-receptor "activlty" at 37 C; and thermostability at 42 C.How- ever, preincubation of the fibroblasts from #99 with 3-10 oM DHT for up to 20h (37 0C) caused no increase in receptor activity (n-S). In contrast, normal fibroblasts doubled their activity (range of 20h/lh values -1.7-2 .8, n-20) . This increase is s upp- ressed by 2 cycloheximide, and is likel y to be a form of "up- regulation" reflecting a larger pool of rec eptor molecules . A similar up-regulation defect has been obs er ved in another pat- ient with partial AR** in whom the activit y showed thermolability and a three-fold greater than normal k- l' The isolated exp ress- ion of a regulatory defect in 199 indicates : (L) that it is fun- ctionally separate from the accompanying thermal and dissociative defects in the other patient; (ii) that 99's mutation probably affected a domain of the androgen receptor mole cule that normal- ly acts as the signal for up-regulation . .*<t Pediatr Rn 14 (4,part 2), 483,1980 1543