Thyroid hormone analogs and fetal goiter.

Transfer of iodothyronine across the placenta in most species occurs only with difficulty. Recently, biologically active, nonhalogenated thyroid hormone analogs have been synthesized with properties which might favor placental transfer. To test this possibility, we compared the doses of T4, T3, and thyroid hormone analogs necessary to prevent propylthiouracil-induced goiter formation in rat fetuses. T4 and T3 prevented fetal goiter, but in doses that caused maternal hyperthyroidism; in contrast, the thyroid hormone analogs prevented fetal goiter in doses that were not thyrotoxic to the mother.

Therapeutic use of pituitary desensitization with a long-acting lhrh agonist: a potential new treatment for idiopathic precocious puberty.

A two year girl with idiopathic true precocious puberty was treated with a long-acting LHRH agonist, D-Trp6-Pro9-NEt-LHRH (LHRHa). Prior to therapy, the patient demonstrated pulsatile gonadotropin secretion during both night and day, a pubertal response to exogenous LHRH, and an elevated plasma estradiol level. After eight weeks of therapy (4 microgram/kg daily), a mean gonadotropin levels fell to the prepubertal range, there was no evidence of pulsatile discharge of gonadotropins nor any response to exogenous LHRH, and plasma estradiol levels became undetectable. No adverse drug reactions were encountered and all effects of therapy were reversed following cessation of treatment for two months. LHRH analogs may offer a new approach to the therapy of idiopathic precocious puberty and merit further study.

Reduced bone mass in reproductive-aged women with endometriosis.

Cortical and trabecular bone masses were measured by quantitative computed tomography of the distal radius in 41 women (30 +/- 1 yr) with endometriosis documented by laparoscopy and compared to those in 35 normal women (32 +/- 1 yr). Hormonal status was assessed, and a subset of 10 women with endometriosis underwent evaluation of calcium absorption and excretion. Menstrual cycles were regular in all women, and hormonal medication had not been administered during the 3 months before evaluation. Estradiol and progesterone varied as expected with the day of the cycle. Fasting calcium excretion was normal. Mean cortical and trabecular bone mass values in women with endometriosis were compared to those in the normal women. Women with endometriosis had significantly decreased cortical and trabecular bone mass. Cortical bone mass in normal subjects was 1263 +/- 11 Hounsfield units (HU), whereas in endometriosis, cortical bone mass measured 1133 +/- 16 HU (P less than 0.0001). Normal trabecular bone mass was 226 +/- 10 HU compared to a mean trabecular bone mass of 173 +/- 9 HU (P less than 0.0001) in endometriosis. Despite the decrease in bone mass documented by quantitative computed tomography, hormonal and calcium dynamics were normal and, therefore, did not appear to be significant etiological factors in regard to the bone loss. Since immunological abnormalities have been reported in association with endometriosis, immune factors may play a role in the development of bone loss in endometriosis and might be of pathogenic significance in this reproductive disorder.

The luteinizing hormone-releasing hormone (LHRH) agonist [D-Trp6-Pro9-NEt]LHRH increased rather than lowered LH and alpha-subunit levels in a patient with an LH-secreting pituitary tumor.

Episodic secretion of LH, and the responses of serum LH, alpha-subunit, and testosterone concentrations to the acute administration of LHRH and the chronic administration of the LHRH agonist analog [D-Trp6-Pro9-NEt]LHRH (D-Trp6-Pro9) were evaluated in a 33-yr-old man previously reported to have an LH-secreting pituitary tumor unaccompanied by FSH hypersecretion. Basal serum LH and alpha-subunit concentrations were elevated [57 +/- 0.7 (SEM) mIU/ml (range, 45-71) and 26 ng/ml, respectively]. Frequent sampling revealed six LH secretory spikes over a 24-h period with increments above basal levels varying from 23-40% and interspike intervals ranging from 1.5-5 h. The concentrations of LH or alpha-subunit after iv administration of 150 micrograms LHRH did not increase above these intrinsic LH secretory increments (delta LH: 23%; delta alpha-subunit: 21%). The low basal serum FSH concentrations (3.5 mIU/ml) and elevated basal serum testosterone levels (1480 ng/dl) were unchanged after LHRH. Administration of clomiphene citrate produced no increase in serum LH, FSH, or testosterone concentrations. An attempt was made to decrease LH secretion in this patient using D-Trp6-Pro9. Administration of 200 micrograms daily sc of this LHRH analog for 21 days was associated with increases in serum LH and alpha-subunit concentrations. Mean serum LH and alpha-subunit levels for the 21 days of analog administration were 110 +/- 5.4 (SEM) mIU/ml (range, 70-170) and 64 +/- 3 (SEM) ng/ml (range, 32-84), respectively. During the 9-day period after discontinuance of the LHRH analog, levels of both serum LH and alpha-subunit declined precipitously and mean serum LH and alpha-subunit levels were 58 +/- 7 (SEM) mIU/ml (range, 18-90) and 22 +/- 3 (SEM) ng/ml (range, 12-44), respectively. We conclude that this patient's pituitary tumor has diminished responsiveness to acute LHRH administration and that the effect of chronic D-Trp6-Pro9 is stimulatory rather than inhibitory, as occurs after chronic administration of this analog to normal subjects. The blunted responsiveness to LHRH administration and the lack of response to clomiphene citrate suggest tumor autonomy. The presence of modest paradoxical responsiveness of serum LH and alpha-subunit concentrations during the course of daily D-Trp6-Pro9 administration suggests that central regulatory mechanisms, if present, are abnormal.

Daily rhythm of plasma melatonin in normal and precocious puberty.

A previous study of normal humans has shown a decrease in plasma melatonin at the onset of puberty, suggesting that melatonin may act to restrain pubertal onset. We have measured plasma melatonin throughout a 24-h period in normal and constitutionally short males at different pubertal stages and in patients with idiopathic true precocious puberty and familial male isosexual precocity. The 24-h profile of plasma melatonin was similar for the prepubertal, pubertal, and adult males studied, with all subjects having low levels (20-50 pg/ml) during the day and high levels (80-100 pg/ml) at night between 0100-0500 h. The 24-h profiles of the patients with isosexual precocity were similar to the profiles observed throughout normal puberty. These data do not support a role for melatonin in the initiation of normal or precocious puberty in man.

Dissociation of adrenarche and gonadarche in precocious puberty and in isolated hypogonadotropic hypogonadism.

Adrenarche is a developmental change of the adrenal gland that results in increased secretion of adrenal androgens. This maturational process generally begins several years before activation of the hypothalamic-pituitary-gonadal axis (gonadarche). To study further the relationship between adrenarche and gonadarche, we examined adrenarche in patients with precocious puberty and in patients with isolated hypogonadotropic hypogonadism. Plasma dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and cortisol were measured basally and during an infusion of ACTH in 50 children with precocious puberty, 5 patients with isolated hypogonadotropic hypogonadism, 7 preadrenarchal children with constitutional short stature, 44 normal pubertal children, and 40 normal adults. Children with precocious puberty did not have a corresponding advance in the timing of adrenarche. Their basal and ACTH-stimulated adrenal androgen levels were markedly lower than those of normal children matched for pubertal stage (P less than 0.05) and were only slightly greater than those reported for normal children of the same age. Similarly, patients with isolated hypogonadotropic hypogonadism and delayed puberty had no corresponding delay of adrenarche. Their adrenal androgen levels were appropriate for chronological age. Thus, these data provide further support for the hypothesis that adrenarche and gonadarche are independent maturational events controlled by separate mechanisms.

Isosexual precocious pseudopuberty secondary to a feminizing adrenal tumor.

We report a 2 10/12-yr-old girl with precocious pseudopuberty due to a feminizing adrenal carcinoma without Cushing's syndrome. The patient had marked elevation of plasma concentrations of the delta 5 adrenal steroids dehydroepiandosterone and dehydroepiandrosterone sulfate and increased levels of androstenedione, estrone, estradiol, and testosterone. Adrenal microsomal 3 beta-hydroxysteroid dehydrogenase-isomerase 17-hydroxylase, 17,20-desmolase, and 21-hydroxylase activities in the tumor and adjacent normal adrenal gland were measured. The tumor had approximately normal levels of 17-hydroxylase and 17,20-desmolase activity, with low levels of 21-hydroxylase and 3 beta-hydroxysteroid dehydrogenase-isomerase activities. This combination of enzyme activity may explain the absence of Cushing's syndrome and the high levels of delta 5 adrenal steroids. This patient demonstrates that adrenal neoplasms arising in girls may mimic isosexual true precocious puberty and should be included in the differential diagnosis of precocious puberty.

Variable response to a long-acting agonist of luteinizing hormone-releasing hormone in girls with McCune-Albright syndrome.

Six girls with McCune-Albright syndrome were treated for at least 2 months with the long-acting LHRH agonist D-Trp6-Pro9-NEt-LHRH, which previously was found to be an effective treatment for true precocious puberty. Nocturnal and LHRH-stimulated serum gonadotropin levels and plasma estradiol levels were measured before treatment and after 2-3 months of treatment. Five of the six girls had no decrease in serum gonadotropin or plasma estradiol levels during therapy, and their pubertal signs were unaffected by treatment. All five of these girls had serum gonadotropin levels that were within or below the normal prepubertal range. The sixth girl, who had gonadotropin levels in the normal pubertal range before treatment, had decreased serum gonadotropin and plasma estradiol levels during 1 yr of LHRH analog therapy. This was associated with cessation of menses and regression of secondary sexual changes. The failure of LHRH analog to modify the course of precocious puberty in the five patients with prepubertal serum gonadotropin concentrations is further evidence that the mechanism of precocious puberty in most girls with McCune-Albright syndrome differs from that in patients with true precocious puberty.

Luteinizing hormone-releasing hormone analog treatment of boys with hypothalamic hamartoma and true precocious puberty.

A long-acting analog of LRH (LRHa) has been shown to suppress pituitary gonadotropin and estradiol secretion to prepubertal levels in girls with idiopathic true precocious puberty. We treated six boys, aged 1-6 yr, with true precocious puberty due to hypothalamic hamartoma for 6-24 months with daily sc injections of LRHa. The patients had enlarged testes (6-25 ml), Tanner stage II-IV pubic hair, facial and axillary hair, increased growth rate, and an advanced bone age. Frequent erections occurred in all patients. Computed tomography of the head showed abnormalities characteristic of hypothalamic hamartoma (0.5-3 cm in diameter) in each boy. Each patient had measurable LH and FSH levels, with pulsed nocturnal secretion, and pubertal LH and FSH responses to LRH. Serum testosterone was in the range for normal adult men (200-600 ng/dl). LRHa significantly decreased basal LH (P less than 0.005) and FSH levels (P less than 0.01), LRH-stimulated gonadotropin levels (P less than 0.005), and serum testosterone levels (P less than 0.005). Testis size decreased significantly (P less than 0.005). Annualized growth velocity (centimeters per yr) decreased significantly compared to the pretreatment growth rate (P less than 0.01). Bone age advancement per yr slowed significantly during the course of LRHa treatment (P less than 0.01). Pubic hair, facial hair, and erections decreased in all patients. LRHa is an effective treatment for boys with precocious puberty associated with hypothalamic hamartoma. Chronic therapy will be required, however, to assess the ultimate effect of LRHa.

Absence of pubertal gonadotropin secretion in girls with McCune-Albright syndrome.

Precocious puberty in girls with McCune-Albright syndrome has been attributed in some cases to early activation of the hypothalamic-pituitary-gonadal axis and in other cases to sex steroid secretion by apparently autonomous ovarian cysts. We evaluated serum gonadotropins and sex steroids in six girls (aged 1-9 yr) with McCune-Albright syndrome. The children had Tanner stage II-IV pubertal development. In five patients, nocturnal gonadotropin concentrations and the gonadotropin response to LHRH were within the normal range for prepubertal children. Thus, the precocious puberty in these patients could not be explained by activation of the hypothalamic-pituitary-ovarian axis. One child had high amplitude nocturnal pulses of serum LH and a LH-predominant response to LHRH. She was the oldest of the six girls and had a bone age of 13.5 yr which is within the range in which hypothalamic-pituitary-ovarian activation normally occurs. The children all had ovarian enlargement and ovarian cysts determined by ultrasound. It appears that precocious puberty in McCune-Albright syndrome may result from ovarian estrogen secretion in the absence of normal pubertal activation of the hypothalamic-pituitary-ovarian axis.

True precocious puberty complicating congenital adrenal hyperplasia: treatment with a luteinizing hormone-releasing hormone analog.

Congenital adrenal hyperplasia (CAH) is a recognized cause of precocious pseudopuberty. Some children with CAH also develop true precocious puberty with early maturation of the hypothalamic-pituitary-gonadal axis. We have seen four such children (three boys and one girl) who had the diagnosis of CAH made between the ages of 3 and 6 yr. These patients were treated with standard doses of hydrocortisone and fludrocortisone. A diagnosis of true precocious puberty was made because of testicular enlargement in the boys, breast development in the girl, progressive pubic hair development, rapid growth, and rapid bone age maturation. Plasma steroid levels were elevated for age, and gonadotropin levels were within the normal pubertal range, both basally and in response to LHRH stimulation. We treated these children with daily sc injections of a LHRH analog (LHRHa) for 6-18 months in addition to the standard hydrocortisone and fludrocortisone therapy for CAH. LHRHa significantly decreased basal plasma LH and FSH, peak LH and FSH responses to native LHRH, and testosterone levels. Testis size decreased in the males, and breast development regressed in the female. LHRHa therapy led to significant decreases in linear growth rate, ulnar growth rate, and rate of bone age advancement. These results suggest that LHRHa is an effective adjunct to hydrocortisone and fludrocortisone in the treatment of true precocious puberty complicating CAH.

24,25 Dihydroxyvitamin D supplementation corrects hyperparathyroidism and improves skeletal abnormalities in X-linked hypophosphatemic rickets--a clinical research center study.

Therapy for X-linked hypophosphatemia (XLH) only partially corrects skeletal lesions and is often complicated by hyperparathyroidism. 24,25(OH)2 D3 improves skeletal lesions in a murine model of XLH and suppresses PTH secretion in animals. Therefore, we undertook a placebo-controlled trial of 24,25(OH)2 D3 supplementation to standard treatment in patients with XLH to improve bone disease and reduce hyperparathyroid complications. Fifteen subjects with XLH receiving standard treatment [1,25(OH)2 D3 or dihydrotachysterol plus phosphate] were evaluated, supplemented with placebo, and reevaluated one yr later. 24,25(OH)2 D3 supplementation was then begun and studies repeated after another year. Each patient underwent a detailed evaluation of calcium homeostasis over a 24-h period. Rachitic abnormalities were assessed radiographically in children. Adults underwent bone biopsies. 24,25(OH)2 D3 normalized PTH values in nine subjects (peak PTH was 46.5 +/- 6.6 pmol/L at entry, 42.3 +/- 5.9 pmol/L after placebo, and 23.3 +/- 5.4 pmol/L after 24,25(OH)2 D3). Nephrogenous cAMP decreased at night, coincident with the decrease in PTH, and serum phosphorus was slightly greater with 24,25(OH)2 D3. Radiographic features of rickets improved during 24,25(OH)2 D3 supplementation in children, and osteoid surface decreased in adults. 24,25(OH)2 D3 is a useful adjunct to standard therapy in XLH by effecting correction of hyperparathyroidism and improvement of rickets and osteomalacia.

Bipolar mood disorder and endometriosis: preliminary findings.

A consecutive sample of 16 women with laparoscopy-diagnosed endometriosis were evaluated for mood disorders. Twelve women met DSM-III criteria for a mood disorder: seven for bipolar disorder, mixed, three for bipolar disorder, manic, and two for major depression. Two women had equivocal diagnoses and two showed no evidence of mood disorder. Nine subjects had first-degree relatives with histories of severe mood disorders.

Familial spastic paraplegia, mental retardation, and precocious puberty.

Two brothers had progressive spastic paraplegia and precocious puberty develop due to Leydig's cell hyperplasia when they were 2 years old. Both later had moderate mental retardation. Family members displayed brisk lower-extremity reflexes and dysarthria in a pedigree that suggested autosomal dominant inheritance with variable expression. Precocious puberty has been associated with other neurologic syndromes. Its occurrence in two brothers with spastic paraplegia has not, to our knowledge, been previously reported.

Duplicate cervix and vagina associated with infertility, endometriosis, and chronic pelvic pain.

BACKGROUND: Müllerian anomalies are associated with several gynecologic complications including endometriosis, infertility, and pelvic pain. CASE: A woman with duplicate cervix and a non-communicating longitudinal vaginal septum, but no other uterine anomalies, presented with pelvic pain, secondary infertility, and a long history of endometriosis. She was treated with operative laparoscopy and excision of the vaginal septum. CONCLUSION: A thorough evaluation, including history, physical examination, and appropriate imaging techniques (hysterosalpingography and magnetic resonance imaging) facilitates accurate diagnosis of anatomical defects and any associated disease in cases of unusual müllerian anomalies. An accurate preoperative diagnosis allows a planned, efficient surgical approach.

Treatment of leiomyomata uteri with leuprolide acetate depot: a double-blind, placebo-controlled, multicenter study. The Leuprolide Study Group.

The purpose of this study was to evaluate efficacy and safety parameters in women with leiomyomata uteri treated with the GnRH agonist leuprolide acetate depot, 3.75 mg intramuscularly every 4 weeks for 24 weeks. One hundred twenty-eight patients were enrolled in a randomized, double-blind, placebo-controlled multicenter study involving 13 investigative centers. Mean uterine volume decreased by 36% at 12 weeks and 45% at 24 weeks of leuprolide therapy. Patients treated with placebo had increased in mean uterine volume of 16% at 12 weeks and 5% at 24 weeks. Seventy-seven percent of leuprolide-treated patients had a more than 25% reduction in uterine volume, compared with 9% of placebo-treated controls. Mean uterine volume returned to pre-treatment size 24 weeks after cessation of leuprolide treatment. The majority of patients had resolution or improvement of their fibroid-related symptoms after 24 weeks of leuprolide treatment. Of 38 leuprolide-treated patients presenting with menorrhagia, 37 (97%) had resolution of this symptom at the time of the final visit. Although 95% of women treated with leuprolide acetate experienced some side effects related to hypoestrogenism, only five patients (8%) terminated treatment prematurely. We conclude that leuprolide acetate depot treatment of leiomyomata uteri is safe and causes significant but temporary reductions in uterine size and fibroid-related symptoms.

Dental development in precocious puberty.

One hundred and one children with precocious puberty were given an oral examination. Dental root development was assessed using panoramic radiographs. All mandibular canines, pre-molars, and molars which could be visualized without apparent distortion were included. The patients were grouped for analysis according to the etiology of their precocity, e.g., McCune-Albright syndrome, familial male, congenital adrenal hyperplasia, central nervous system lesions, and idiopathic precocious puberty. Dental development was significantly retarded relative to their chronological age in patients with idiopathic precocious puberty. However, no significant abnormal dental development was detected in any of the other groups. Individual oral-facial growth and development remain the primary considerations for timing orthodontic treatment.

Are women being counseled about estrogen replacement therapy?

The U.S. Preventive Services Task Force and several medical professional associations have published guidelines recommending that all women be counseled around the time of menopause about the benefits and risks of estrogen replacement therapy (ERT) so that they may make an informed decision about its use. Despite the proliferation of ERT counseling guidelines, little is known about whether these guidelines are being followed. There were 1,500 female members (aged 40 to 69) of a Northeastern U.S. Independent Practice Association--model Health Maintenance Organization who were surveyed, and 51 percent reported that a health care provider had talked with them about the benefits and risks of ERT. In multivariate analyses, a woman's demographic characteristics (age, race, income), stage of menopause, severity of menopausal symptoms, and body weight were the major correlates of receipt of ERT counseling. Women at greater risk for osteoporosis or heart disease were no more likely to be counseled, although those with diagnosed osteoporosis were. What appear to be selective ERT counseling practices will need to be modified if the goal of providing universal ERT counseling to midlife women is to be attained.

High-field MRI and US evaluation of the pelvis in women with leiomyomas.

Magnetic resonance imaging (MRI) and real-time transabdominal ultrasonography (US) were performed on 23 women with uterine leiomyomas. The uterus, ovaries, and cul de sac were evaluated. Accurate determination of uterine volume was possible in all cases by MRI, but was limited on US in uteri larger than 140 cc. Marked enlargement also prevented visualization of contour abnormalities in eight patients on US, but none on MRI. The endometrial stripe and junctional zone could not be adequately visualized in 21/23 US examinations, whereas they were identified in all 23 MRI (8 normal and 15 distorted). Individual leiomyomas were clearly depicted on 4 US and 19 MR scans, the smallest being 1.1 cm and 0.8 cm, respectively. Of the 31 fibroids present on MRI: 13 were intramural, 4 subserosal, and 14 submucosal. MRI successfully identified 44/46 ovaries as compared to 21/46 on US. Cul de sac fluid was noted in seven women by MRI alone. This data suggests that MRI is superior to US in examination of the entire pelvis in women with leiomyomas.

Thermal stability of a long-acting analogue of luteinizing hormone releasing hormone (D-trp6-pro9-NEt-LHRH).

The stability of solutions of a long-acting analogue of luteinizing hormone releasing hormone (D-trp6-pro9-NEt-LHRH [LHRHa] after heating to 60C for 5 days, after repeated freezing and thawing, and after refrigeration at 4C for 8 days has been examined. None of the treatments caused a detectable alteration in the HPLC profile, and none caused a significant change in biological activity in vivo. It is concluded that D-trp6-pro9-NEt-LHRH can withstand mild heating, repeated freezing and thawing, and short-term refrigeration without apparent change in HPLC profile or biological activity. It is also concluded that the results obtained with the HPLC method correlate well with the results from the in vivo bioassay.

PIP: The stability of solutions of a long acting analogue of luteinizing hormone releasing hormone (D-trp6-pro9-NEt-LHRH [LHRHa]) after heating to 60 degrees Centigrade for 5 days, after repeated freezing and thawing, and after refrigeration at 4 degrees Centrigrade for 8 days was examined. The treatments administered to solutions 2 (60 degrees Centigrade x 5 days), 4 (7 freeze thaw cycles), and 5 (4 degrees Centigrade x 8 days) did not cause any change in the retention time or absorbance (at 210, 230, and 271 nm) of their HPLC profiles when compared to the control solutions 1 and 3. Control solutions degraded with sodium hydroxide (6) showed no LHRHa peak. A 1:1 mixture of the degraded and control solutions (7) gave a peak height of LHRHa that was 51.2% of control. Each of the 5 solutions showed similar biological activity. No effect was seen at a dose of 8 ng, whereas 24 ng caused a significant LH rise (218-277% of the basal level) for each solution. The parallel line potency estimate for solution 2 (60 degrees Centigrade x 5 days) relative to solution 1 was 0.77 (95% confidence limits, 0.32-1.48). The potency ratio for solution 4 (7 freeze thaw cycles) relative to solution 3 was 0.85 (95% confidence limits, 0.23-2.26). In sum, the D-trp6-pro9-NEt-LHRH can withstand mild heating, repeated freezing and thawing, and short term refrigeration without apparent change in HPLC profile or biological activity. The results obtained with the HPLC method correlate will with the results from the "in vivo" bioassay.