Published data on the influence of hypothyroidism on fertility, gestation, and the offspring are controversial. We studied nine hypothyroid women during 11 pregnancies. Mean serum values for thyroxine, triiodothyronine (T3), resin T3 uptake ratio, and thyroid-stimulating hormone were 2.3 microgram/dL, 82 ng/dL, 0.64, and 105 mU/mL, respectively. Four patients had iatrogenic hypothyroidism (three remote thyroidectomy, one remote 131I therapy), two Hashimoto's thyroiditis, and three idiopathic primary hypothyroidism. Seven patients first presented untreated after the 24th week of gestation. Two patients needed cesarean section; seven delivered vaginally. There was one stillborn infant in the only patient with pre-eclampsia. Another infant had Down's syndrome and an ostium primum defect (mother's age, 41 years). The remaining nine infants were normal at birth. All placentas were normal. Follow-up in seven infants up to 2.7 years showed normal thyroid function and somatic development. Infants of hypothyroid mothers may be normal because their hypothalamic-pituitary thyroid axis develops independently from the mother.
Although human GH (hGH) has been administered to GH-deficient patients for over 20 yr, there are minimal published data on the relationship of response to dose. We have given hGH on the basis of body weight to 93 prepubertal GH-deficient patients over an initial 12 months of therapy. Their annual growth rate while receiving hGH was 5.58 +/- 2.30 (+/- SD) cm at a dose of 30 mIU/kg, three times a week (tiw; n = 27); 7.31 +/- 1.75 (+/- SD) cm at a dose of 60 mIU/kg, tiw (n = 38); 7.22 +/- 3.12 (+/- SD) cm at a dose of 80 mIU/kg, tiw (n = 12); and 8.94 +/- 1.19 cm (+/- SD) at a dose of 100 mIU/kg, tiw (n = 16). Doubling the dose from 30 to 60 mIU increased the mean rate of growth 1.3 times, and increasing the 30 mIU dose by a factor of 3.3 increased the mean rate of growth 1.6 times. The response (y) as a function of the log-dose (x) is defined by the equation y = -3.12 + 5.80 log x. When the effect of hGH is expressed as the increase in growth rate while receiving therapy, the log-dose relationship is defined by the equation y = -6.09 + 5.67 log x. This dose-response curve provides data which are useful in choosing the best dose of hGH for an individual patient. It also allows a more accurate projection of the costs and benefits of hGH therapy.
We have previously demonstrated that the tissue-specific regulation of human aromatase cytochrome P450 (P450arom) gene expression is, in part, the consequence of the use of tissue-specific promoters. Promoter I.1 (PI.1) and PI.2-specific transcripts are expressed in the placenta, whereas promoter II (PII) appears to be the only active promoter in the corpus luteum. Testicular and ovarian sex cord tumors with annular tubules (SCTATs) associated with gynecomastia in prepubertal boys and isosexual precocity in girls with Peutz-Jeghers syndrome (P-JS) have been previously reported. In the present study, we investigated the regulatory elements directing P450arom gene transcription in samples of SCTAT from three prepubertal boys and a girl with P-JS and an ovarian granulosa cell tumor from an adult woman, as well as in healthy fetal and adult testicular and ovarian tissues. Placental tissue was used as a control. Using polymerase chain reaction linked to reverse transcription and northern blotting, we determined the tissue-specific use of various P450arom promoters by analyzing specific 5'-termini from messenger RNA templates. Results indicate a universal gonadal promoter (PII) directs P450arom gene expression in healthy fetal and adult ovaries and testes, as well as in SCTAT of the P-JS and an adult ovarian granulosa cell tumor. These results are interpreted to mean that use of PII in human ovary and testis is preserved from the fetal period into adult life as well as in transformed neoplastic Sertoli and granulosa cells. On the other hand, transcripts from placenta are specific for PI.1 (and to a much lesser extent, PI.2). In SCTAT, immunoreactive P450arom is detected only in the cytoplasm of neoplastic cells, whereas the normal-appearing sex cords do not contain any immunoreactive P450arom. These results further suggest that the markedly increased aromatase expression of these transformed neoplastic cells is not a consequence of using different tissue-specific promoters. Rather it appears to involve activation (or failure of inhibition) of the upstream regulatory elements of the same promoter, which is normally functional in all gonadal tissues, namely the proximal PII.
We have studied 71 sexually immature growth hormone (GH) deficient patients treated for 1 yr with human growth hormone (hGH). Nineteen patients had growth hormone deficiency secondary to an organic lesion. In 52 there was no demonstrable underlying cause. Patients with organic disease received thyroxine 0.2 mg/ M 2 /24 hr, cortisone acetate 20 mg/M 2 /24 hr, and 2 units hGH 3 times weekly from either unembalmed or embalmed pituitaries. These 2 groups grew (in cm/yr, mean ± 1 SD) 5.4 ± 2.8 and 7.0 =fc 2.8, respectively. Patients with idiopathic disease received hGH from unembalmed pituitaries. One group was given thyroxine, cortisone acetate and hGH 2 units 3 times weekly, a second only hGH 2 units 3 times weekly, and a third only hGH 10 units 3 times weekly. These groups grew 7.3 ± 3.5, 9.3 ± 2.3 and 11.9 i t 2.5 cm/yr, respectively. Embalmed hGH was as effective as unembalmed. The underlying cause of GH deficiency did not influence the degree of response. While the addition of cortisone and thyroxine did not clearly affect the response to hGH, this combination therapy was associated with an acceleration of bone age in excess of the advance in height age. A significantly greater response was observed in patients receiving hGH 10 units 3 times weekly. The amount of growth correlated with pretreatment height and weight; a greater response was observed in smaller children. While 2/3 of the patients responded well, 1/3 failed to increase their growth rate to greater than 7 cm/yr and/or to double their pretreatment growth rate. (/ Clin Endocrinol Metab 35: 483, 1972) A LTHOUGH human growth hormone (hGH) had been isolated from pitu-
In humans, mutations in the testis-determining gene SRY result in XY sex reversal with pure gonadal dysgenesis (PGD). However, only about 10-15% of the cases of PGD can be explained by mutations within the SRY open reading frame, suggesting the existence of other sex-determining genes. Although SRY is known to bind and bend DNA, its target and mode of action remain elusive. Here, we describe a novel mutation in SRY at codon 127, resulting in a tyrosine (Y) to phenylalanine (F) substitution in the protein. This sequence variant was found not only in the XY female patient but also in her father, who is a phenotypically normal male. However, this Y127F variant was not found in the SRY sequences of 93 other randomly chosen males. This substitution affects a highly conserved tyrosine residue in the HMG box of SRY, in which two de novo mutations have been described previously in XY females with PGD. Furthermore, electromobility shift studies demonstrate that SRY protein harboring the Y127F variant is incapable of binding consensus SRY binding sites in vitro. Taken together, these data suggest that the Y127F variant is a novel mutation with functional consequences and not simply a polymorphism. The allelic variant of SRY transmitted in this family and shared by both a phenotypic female (proband) and a phenotypic male (proband's father) emphasizes the importance of modifier genes in the sex determination pathway.
The concentrations of LH and FSH were determined in serum samples obtained at 15 min intervals during a 4 h period from seven normal girls, 9.5-16.5 years of age, and eight normal boys, 9.0-16.8 years of age. An episodic pattern of LH secretion was found in all subjects. There was no significant (P greater than 0.1) difference between girls and boys as to number of episodes (3.0 +/- 0.6 vs. 3.0 +/- 0.0 per 4 h), absolute LH increase (2.6 +/- 1.1 vs. 2.4 +/- 1.0 mIU per ml) or "apparent LH half-life" (64.3 +/- 20.8 vs. 76.1 +/- 23.4 min). Mean absolute increase during secretory episodes correlated (R = 0.89, P less than 0.005) with the mean LH concentration per 4 h, and a significant (P less than 0.025) inverse correlation (R = -0.52) was found between the mean per cent increment of the LH secretory episode and the mean "apparent LH half-life." Minor fluctuations of FSH were also observed. In girls and boys, the mean concentration of both gonadotropins increased with advancing puberty. The increase in LH concentration was due to an increase in the amplitude of secretory episodes rather than to an increase in the number of episodes. The increase in FSH concentration reflected a consistent elevation throughout the period of sampling.
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