Effects of o,p'-DDD on pituitary-gonadal function in patients with Cushing's disease

O,p'-DDD has a cytotoxic action and inhibits the cholesterol side chain cleavage enzyme, 11 beta-hydroxylase, 3 beta-hydroxysteroid dehydrogenase coupled with delta 5 to 4 isomerase and 21-hydroxylase of the adrenal cells. However, the effects of o,p'-DDD on gonadal steroidogenesis are still unknown. In the present study, the effects of o,p'-DDD on Plasma cortisol, pregnenolone, 17 alpha-hydroxypregnenolone (17-OH-pregnenolone), progesterone, 17 alpha-hydroxyprogesterone (17-OH-progesterone), 11-deoxycorticosterone (DOC), corticosterone, dehydroepiandrosterone (DHEA), delta 4-androstenedione (androstenedione), estradiol, and LH and FSH were investigated in 3 patients with Cushing's disease before and after the administration of o,p'-DDD. The results are presented here. In Case 1 (18 yr old female) who had had secondary amenorrhea for 2 years, the plasma levels of cortisol, pregnenolone, 17-OH-pregnenolone, DHEA, androstenedione, testosterone, estradiol and corticosterone were elevated. The basal levels of plasma LH and FSH and the responses of both gonadotropins were lower than those of women with eumenorrhea. The plasma levels of progesterone, DHEA and testosterone decreased to normal 2 months after the beginning of the administration of o,p'-DDD. She restored menstrual cycles ranging from 40 to 50 days 3 months after the administration of o,p'-DDD, but with anovulatory bleeding. She showed a biphasic body temperature pattern with plasma progesterone and estradiol levels indicating corpus luteum formation 11 months after the start of the treatment, when plasma cortisol as well as progesterone and androgen were reduced to normal. The basal levels of FSH and LH and responses of these gonadotropins were slightly improved at that time. The plasma levels of cortisol, DHEA and androstenedione were high in Case 2 (38 yr old male) and Case 3 (45 yr old male), whereas plasma testosterone level was normal in Case 2 and low in Case 3. The plasma levels of these 3 steroids were normalized 28 days after the beginning of the o,p'-DDD administration. These results suggest that o,p'-DDD does not interfere with gonadal steroidogenesis in Cushing's disease.     

Virilizing adrenal tumor in a child suppressed with dexamethasone for three years. Effect of o,p'-DDD on serum and urinary androgens.

Extensive hormonal evaluation was performed in a girl with adrenal carcinoma during the primary tumor stage, following adrenalectomy, during the period when metastases were evident and while on treatment with o,p'-DDD. At the age of 14 months a diagnosis of congenital adrenal hyperplasia was made and treatment with dexamethasone (0.125 to 0.25 mg/day) resulted in a fall-off in growth rate, normal advancement in bone age, decrease in virilization and suppression of 17- ketosteroid excretion which continued until 4 3/12 years of age when virilization increased. At five years of age elevated serum and urinary androgen levels unsuppressible with dexamethasone were noted. Following removal of a large right adrenal carcinoma, serum and urinary hormone levels returned to normal. There months following surgery, liver metastases were documented associated with elevated levels of serum androgens. With o,p'-DDD treatment, serum dehydroepiandrosterone sulfate (DS) and urinary 17-ketosteroid (17-KS) excretion fell rapidly while there was a delay in the fall of free androgens. The persistence of free steroid secretion with decreased formation of DS suggests that the o,p'-DDD may have altered sulfatase activity before causing tumor necrosis and total decrease in steroidogenesis.     

The effects of o,p'-DDD on human adrenal steroid synthesis

In the present study, the effects of o,p'-DDD on plasma levels of pregnenolone, 17 alpha-hydroxypregnenolone, progesterone, 17 alpha-hydroxyprogesterone, 11-deoxycorticosterone, deoxycortisol, corticosterone, cortisol, androstenedione and testosterone were studied in 6 patients with adrenal carcinoma (3 with Cushing's syndrome, 2 with adrenogenital syndrome, one without clinical manifestation) and 6 with Cushing's disease. Plasma levels of these steroids were decreased in all of the patients with adrenal carcinoma. The decrement of progesterone and 17 alpha-hydroxyprogesterone was greater than that of pregnenolone and 17 alpha-hydroxypregnenolone. These results indicate that o,p'-DDD inhibits both cholesterol cleavage enzyme and 3 beta-hydroxysteroid dehydrogenase coupled with delta 5 to 4 isomerase system. Plasma levels of pregnenolone and 17 alpha-hydroxypregnenolone showed a twofold increase on the 7th day after consecutive administrations of o,p'-DDD in patients with Cushing's disease. Plasma levels of cortisol were decreased to normal one month after continuous o,p'-DDD treatment. Urinary 17-OHCS and 17-KS have been decreased out of proportion to the decrease in plasma cortisol in the first week of o,p'-DDD treatment. Such a disparity suggests that o,p'-DDD might affect the extra-adrenal metabolism of cortisol. However, no evidence was found for the inhibition of hepatic C17-20lyase and glucuronyl transferase. Regression of pulmonary metastases was observed in one case with Cushing's syndrome due to adrenal carcinoma, suggesting that o,p'-DDD causes necrosis of the metastatic adrenal carcinoma. A remission of the disease was obtained in one patient with Cushing's disease after 6 months of continuous o,p'-DDD treatment. The usefulness of o,p'-DDD for the treatment of adrenal carcinoma with metastases and Cushing's disease was confirmed.     

THE EFFECT OF o,p''-DDD ON ADRENAL STEROID REPLACEMENT THERAPY REQUIREMENTS

Two patients with adrenal carcinoma treated with 2,2-bis (2-chlorophenyl-4-chlorophenyl)-1,1-dichloroethane (o,p'-DDD) as adjuvant therapy were studied. Both patients developed hypoadrenalism while on o,p'-DDD and apparently adequate dexamethasone replacement therapy. The hypoadrenalism was overcome by increasing steroid replacement therapy. Dexamethasone levels were measured in the serum by radioimmunoassay and shown to be lowered by o,p'-DDD therapy. A study of the absorption and disappearance of dexamethasone from the circulation in response to a (1 mg oral dose indicated that the steroid was absorbed normally but was cleared more rapidly from the circulation of these two patients than from normal controls. This may be due to a change in the type of metabolites excreted. It is suggested that many of the reported side-effects of o,p'-DDD may be due to hypoadrenalism and may be controlled by greatly increasing the steroid replacement dose. The adequacy of corticosteroid replacement therapy may best be assessed by monitoring the levels of ACTH.     

Mitotane increases the radiotherapy inhibitory effect and induces G2-arrest in combined treatment on both H295R and SW13 adrenocortical cell lines

Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane (o,p'-DDD) is an agent with adrenotoxic effect, which is able to block cortisol synthesis. This drug and radiotherapy are used also in adrenal cancer treatment even if their biological action in this neoplasia remains unknown. We investigated the effects of o,p'-DDD and ionizing radiations (IR) on cell growth inhibition and cell cycle perturbation in H295R and SW13 adrenocortical cancer cells. Both cell lines were irradiated at a 6 Gy dose and were treated with o,p'-DDD 10(-5) M separately and with IR/o,p'-DDD in combination. This combination treatment induced an irreversible inhibition of cell growth in both adrenocortical cancer cells. Cell cycle analysis showed that IR alone and IR/o,p'-DDD in combination induced the cell accumulation in the G2 phase. At 120 h after IR, the cells were able to recover the IR-induced G2 block while cells treated with IR/o,p'-DDD were still arrested in G2 phase. In order to study the molecular mechanism involved in the G2 irreversible arrest, we have considered the H295R cell line showing the highest inhibition of cell proliferation associated with a noteworthy G2 arrest. In these cells, cyclin B1 and Cdk2 proteins were examined by western blot and Cdk2 kinase activity measured by assay kit. The H295R cells treated with IR/o,p'-DDD shared an increase in cyclin B1 amount as the coimmunoprecipitation of Cdc2-cyclin B1 complex. The kinase activity also shows an increase in the treated cells with combination therapy. Moreover, in these cells, sequence analysis of p53 revealed a large deletion of exons 8 and 9. The same irreversible block on G2 phase, induced by IR/o,p'-DDD treatment, happened in H295R cells with restored wild-type p53 suggesting that this mechanism is not mediated by p53 pathway.     

The effects of o,p'-DDD on adrenal steroidogenesis and hepatic steroid metabolism

O,p'-DDD is used for the treatment of adrenocortical carcinoma and Cushing's disease. The inhibitory effect of this drug on the adrenal steroid biosynthesis has been described by many authors, but there are very few reports about the sites of action of this drug on adrenal steroid synthesis. This paper presents in vitro studies on adrenal steroidogenesis and hepatic steroid metabolism. The effects of o,p'-DDD on adrenal 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 11 beta-hydroxylase (11 beta-OHlase) and 18-hydroxylase (18-OHlase) were examined in vitro using mitochondrial and microsomal fractions prepared by standard centrifugation procedures from the homogenate of bovine adrenal cortices. The concentrations of o,p'-DDD inducing 50% inhibition of 3 beta-HSD, 11 beta-OHlase and 18-OHlase were 8 X 10(-6) M, 1 X 10(-5) M and 3 X 10(-6) M, respectively. This study clearly demonstrates the marked inhibitory effects of o,p'-DDD on 3 beta-HSD in vitro, which was not described previously. The inhibitory effects of o,p'-DDD on these 3 enzymes were diminished by an addition of 0.05 approximately 0.5 mM of cofactor (NADPH or NAD). The results indicate that o,p'-DDD may reduce NADPH or NAD utilization, resulting in the inhibition of steroidogenesis. The effects of o,p'-DDD on hepatic 5 beta-reductase were examined in vitro using rat liver homogenate. O,p'-DDD inhibits 5 beta-reductase, resulting in the decrease of conversion of cortisol to dihydrocortisol and tetrahydrocortisol at the concentration of 10(-3) M.     

Glucocorticoid and mineralocorticoid pathways in two adrenocortical carcinomas: comparison of the effects of o,p'-dichlorodiphenyldichloroethane, aminoglutethimide and 2-p-aminophenyl-2-phenylethylamine in vitro.

The synthesis of glucocorticoids and mineralocorticoids in vitro was studied in an adrenocortical carcinoma after alblation from an 11.5-year-old boy. This patient had been unsuccessfully treated with high doses of o,p'-dichlorodiphenyldichloroethane (o,p'-DDD) and aminoglutethimide. These in-vitro results were compared with those obtained with another adrenocortical carcinoma removed from a 26-year-old woman who had received no preoperative treatment. The sensitivity of these adrenocortical carcinomas to o,p'-DDD, aminoglutethimide and 2-(p-aminophenyl)-2-phenylethylamine (SKF 12185) was investigated. Synthesis of cortisol (47%) and corticosterone (45%) in control incubations showed that 11 beta-hydroxylase activity was not affected by the treatment. This explains the raised level of plasma cortisol in the treated child. All three compounds inhibited both 11 beta-hydroxylase and 18-hydroxylase activities up to 95%, depending on the inhibitor. This study shows (a) an inhibitory effect of o,p'-DDD on the steroidogenesis of an adrenocortical carcinoma in vitro, an effect not previously reported in man or laboratory animals, and (b) the in-vitro efficacy of o,p-DDD and aminoglutethimide on corticosteroidogenesis by a carcinoma unresponsive to treatment in vivo. This discrepancy between data obtained in vivo and in vitro could possibly be explained by either an insufficient ratio of ingested dose: tumour mass, or a malabsorption of the drugs in this patient.     

The protracted effect of o,p'-DDD in Cushing's disease and its impact on adrenal morphogenesis of young human embryo

We hereby present a patient with Cushing's disease who became pregnant while being treated with o,p'-DDD and underwent a therapeutic abortion in view of the known embryotoxicity and placental transfer of this drug. Biopsy of adipose tissue in this patient showed it to be the storage site of considerable quantities of o,p'-DDD. Serum levels of o,p'-DDD determined in this patient initially four months after withdrawal of treatment and in another similar case three months after withdrawal were about 20 times higher than those found in untreated patients and reached control values only about 20 months later. Repeated evaluation of plasma and urinary free cortisol failed to reveal any correlation with the serum levels of o,p'-DDD, suggesting that the drug blood values cannot be used as a reliable indicator of the therapeutic effect on the adrenal gland. The histopathological examination of the embryo, aged about 42 days, revealed a dysmorphogenic event in the cortical primordia characterized by pycnotic sympathoblasts. It is suggested that such a toxic effect of o,p'-DDD on the embryonic cortical cells may act indirectly, affecting the viability of the migrating sympathoblasts.     

Sustained remission of metastatic adrenal carcinoma during long-term administration of low-dose mitotane

We present our experience with two female patients suffering from metastatic, recurrent adrenocortical carcinomas, to whom o,p'-DDD (mitotane) was administered for unusually long duration. The first patient received mitotane as monotherapy after relapse (in doses ranging from 3 to 6 g/day initially and 1 g/day thereafter, for 13 yr). The second patient presented with metastatic disease and underwent radical surgical excision of the adrenal. Mitotane was administered initially at 2.5 g/day, and the dose was gradually lowered over 8 yr to 1 g/day, without interruption. Both patients tolerated the medication well, regardless of the daily dosage, with complaints limited to epigastric pain and nausea, while their disease has been kept under control for 14 and 16 yr, respectively. The blockade of steroid synthesis with mitotane resulted in hypercholesterolemia in both patients and in premature menopause in the second patient; however, these abnormalities were taken care of with the appropriate therapy. The excellent follow-up of these patients suggests that even in hopeless cases with metastatic adrenocortical carcinoma, mitotane should be administered for very long periods of time as it can be well-tolerated and may be beneficial in the long run.     

Metabolism of o,p'-DDD (mitotane) in human and animals. Actual notions and practical deductions (author's transl)]

The metabolism of o,p'-DDD (mitotane), a well-known inhibitor of adrenal steroidogenesis in man and animal, is reviewed. Following oral administration, about 65% of the ingested drug were found to pass in the stool. The drug appeared in the urine in metabolized forms: o,p'-DDA and mono-and dihydroxylated derivatives of o.p'-DDA. These latters were found as well in the stools. An unsaturated metabolite, o,p'-DDE was described in plasma and tissues in man. Serum specimens of treated patients were analyzed for o,p'-DDD during various phases of therapy: the levels and the rate of rise during treatment were very variable (5 to 90 microng/ml). Tissue levels were obtained from animals (rats, dogs) or men (biopsy as well as autopsy): o,p'-DDD was primarily found stored in adipose tissue and fat-containing tissues, essentially adrenals. Practical conclusions can be drawn from these results: there is no correlation between the dose of o,p'-DDD administered and its blood level; there is no correlation between blood levels and the patient's responsiveness to the drug; there is a possibility that the molecule transformed in an active metabolite through its metabolism.     

RECOVERY OF ADRENAL FUNCTION AFTER TREATMENT OF ADRENOCORTICAL CARCINOMA WITH o,p''-DDD

The adrenolytic agent, 2,2-bis[2-chlorophenyl-4-chlorophenyl] 1,1 dichloroethane (o,p'-DDD), was used over a 20-month period following surgery in a 2 3/12-year-old girl for treatment of adrenocortical carcinoma. The child remained free of disease and was maintained on glucocorticoid and mineralo-corticoid supplements for 7 years. Hormonal evaluation was undertaken at 9 9/12 years of age to determine remaining adrenal steroidogenic capacity. Following discontinuation of both hydrocortisone and 9 alpha-fludrocortisone, she remained stable and asymptomatic. Immediately after discontinuing 9 alpha-fludrocortisone, the adrenal glomerulosa was able to respond to stimulation by the renin-angiotensin system as shown by the ability to achieve renal sodium conservation on a restricted sodium intake (less than 10 mEq/d for 5 d). The response of the adrenal fasciculata to ACTH stimulation showed a slower recovery. Baseline levels of cortisol were in the low normal range, but there was no increase in plasma cortisol or urinary 17-hydroxysteroids following stimulation with ACTH. The responses of cortisol, deoxycorticosterone, and corticosterone to ACTH stimulation gradually improved to achieve normal stimulated levels 18 months after stopping medications. Serum testosterone and delta 4-androstenedione were initially increased for level of puberty, while levels of dehydroepiandrosterone were prepubertal. Testosterone and delta 4-androstenedione did not suppress with dexamethasone (2 mg/d for 2 d; 4 mg/d for 2 d), and dehydroepiandrosterone decreased only slightly. However, administration of norethindrone (Norlutin) (10 mg orally, three times a day for 3 d) resulted in suppression while human chorionic gonadotrophin (hCG; 5000 U i.m. daily for 3 d) produced stimulation of testosterone, delta 4-androstenedione and dehydroepiandrosterone. Thus the androgens were felt be predominantly of ovarian origin. Dehydroepiandrosterone rose to low normal levels by 18 months after discontinuation of hydrocortisone. We thus demonstrate for the first time that both the adrenal glomerulosa and fasciculata have the capacity to recover normal function following treatment with o,p'-DDD. Further, we suggest that early exposure to excess adrenal androgens may result in mild alteration of gonadal function.     

Analysis of the relationship between disease activity and damage in patients with systemic lupus erythematosus--a 5-yr prospective study

OBJECTIVE: To determine whether initial damage, disease duration, age, initial health status, average disease activity over the 5 yr or an average medication score covering the follow-up period would predict an increase in damage in patients with systemic lupus erythematosus (SLE) within the next 5 yr. METHODS: A 5-yr prospective longitudinal study of a cohort of 141 consecutive patients with SLE attending a specialist lupus out-patient clinic in London from their first assessment between July 1994 and February 1995. Disease activity was assessed using the BILAG system, initial health status by the Medical Outcome Survey Short Form 20 with an extra question about fatigue (SF-20+) and damage by the SLICC/ACR Damage Index (SDI). Damage was reassessed 5 yr later. Statistical analysis was carried out using multiple logistic regression analysis (logXact). RESULTS: One hundred and thirty-three female and eight male SLE patients (97 Caucasians, 16 Afro-Caribbeans, 22 Asians and 6 others) were included, their age at inclusion was 41.1 +/- 12.5 yr and their disease duration 10.2 +/- 6.3 yr. The mean measures at inclusion were: total BILAG 5.2 (range 0-17), total SDI 1.2 (0-7) and medication score 1.2 (0-3). Six patients were lost to follow-up because they had moved. Of the remaining 135 patients total damage had increased in 40 patients and 10 patients had died. At the end of the study, at 4.63 +/- 0.19 yr, the total SDI had increased to 1.6 +/- 1.7. Multiple logistic regression analysis revealed that death and increase in damage were strongly predicted by a high total disease activity over the entire study period (P<0.001) as we had hypothesized. When the total BILAG score was replaced by the average number of A-flares the prediction of accrual of damage during the study period was again highly significant (P = 0.004). CONCLUSIONS: In this first prospective study of its type a highly significant impact of total disease activity, as measured over 5 yr using the BILAG system, on the development of total damage was revealed. Moreover, these results provide further proof of the validity of the SDI and support the BILAG concept of the A-flares.     

IN VITRO BIOSYNTHESIS OF 1 8-HYDROXY-l l-DEOXYCORTI-COSTERONE FROM DEOXYCORTICOSTERONE BY HUMAN ADRENAL GLANDS REMOVED FROM PATIENTS WITH HYPERCORTICISM

The biosynthesis of 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) was studied by in vitro incubations of human adrenals resected from patients with Cushing's syndrome, using deoxycorticosterone as precursor. 18-OH-DOC synthesis was similar in adrenals from normal subjects and in those derived from patients with different types of Cushing's syndrome (hyperplasia, adenoma, carcinoma). The in vitro addition of o,p'-DDD (5 x 10(-3) M) to an adrenocortical carcinoma incubation did not alter 18-OH-DOC biosynthesis. By contrast, treatment of the patient with o,p'-DDD prior to adrenalectomy resulted in a low production of 18-OH-DOC in vitro but only when cortisol synthesis was drastically decreased.     

A case of adrenocortical carcinoma associated with recurrence after laparoscopic surgery

Laparoscopic adrenalectomy has become increasingly popular because of its minimally invasive nature, but guidelines for selection of cases suitable for this surgical procedure have not been established. We report a 52-year-old woman with adrenocortical carcinoma, manifesting as Cushing's syndrome, treated with laparoscopic adrenalectomy. The tumour was removed in toto and had been histologically diagnosed as adrenocortical adenoma. However, the patient developed intra-abdominal peritoneal dissemination of carcinoma 15 months after surgery. Review of the histopathological findings of the resected adrenocortical tumour revealed that the neoplasm met five out of nine histological criteria for adrenocortical malignancy, and was diagnosed as adrenocortical carcinoma. Histopathological examination of the tumour was also consistent with adrenocortical carcinoma. The patient responded extremely well to chemotherapy, including carboplatin, etoposide and o,p'-DDD (1,1-dichlorodiphenyldichloroethane), and a subsequent CT (computed tomography) scan 12 months after the start of chemotherapy demonstrated no evidence of disease. However, the patient developed neurological impairment, including dysarthria, as a side-effect of o, p'-DDD. The patient died of aspiration pneumonia due to a decreased pharyngeal reflex. Postmortem examination revealed no foci of residual carcinoma. This case report emphasizes the importance of excluing possible adrenocortical malignancy in patients considered for laparoscopic adrenalectomy, histopathological diagnosis of adrenocortical malignancy and careful monitoring for neurotoxicity during o,p'-DDD treatment.     

Natural history, treatment, and course of papillary thyroid carcinoma

We have analyzed the course of papillary thyroid carcinoma in 269 patients managed at the University of Chicago, with an average follow-up period of 12 yr from the time of diagnosis. Patients were categorized by clinical class; I, with intrathyroidal disease; II, with cervical nodal metastases; III, with extrathyroidal invasion; and IV, with distant metastases. Half of the patients had a history of thyroid enlargement known, on the average, for over 3 yr. In 15% of patients given thyroid hormone, the mass decreased in size. The peak incidence of cancer was when subjects were between 20-40 yr of age. Tumors averaged 2.4 cm in size; 21.6% had tumor capsule invasion, and 46% of patients had multifocal tumors. Sixty-six percent of the patients had near-total or total thyroidectomy. The overall incidence of postoperative hypoparathyroidism was 8.4%, but the incidence was zero in 83 near-total or total thyroidectomies carried out by 1 surgeon. Twenty-five percent of the patients had continuing or recurrent disease, and 8.2% died from cancer. Deaths occurred largely in patients with class III or IV disease. Cervical lymph nodes were associated with increased recurrences, but not increased deaths. Extrathyroidal invasion carried an increased risk of 5.8-fold for death, and distant metastases increased this risk 47-fold. Age over 45 yr at diagnosis increased the risk of death 32-fold. Tumor size over 3 cm increased the risk of death 5.8-fold. Surgical treatment combining lobectomy plus at least contralateral subtotal thyroidectomy was associated, by Cox proportional hazard analysis, with decreased risk of death in patients with tumors larger than 1 cm and decreased risk of recurrence among all patients, including patients in classes I and II, compared to patients who underwent unilateral thyroid surgery or bilateral subtotal resections. By chi 2 analysis, 131I ablation of residual thyroid tissue after operation was associated with decreased risk of recurrence in tumors larger than 1 cm and decreased risk of death in patients in classes I and II with tumors more than 1 cm in size. The data strongly support the use of more extensive initial surgery in class I and II patients with tumors more than 1 cm in size as well as postoperative radioactive 131I ablation of thyroid remnant tissue.     

Long-term observation of 87 girls with idiopathic central precocious puberty treated with gonadotropin-releasing hormone analogs: impact on adult height, body mass index, bone mineral content, and reproductive function

OBJECTIVE: We assessed in a retrospective unicenter study the impact of treatment with GnRH analogs (GnRHa) on adult height (AH), body mass index (BMI), bone mineral density (BMD), and reproductive function in girls with idiopathic central precocious puberty (ICPP). PATIENTS: Eighty-seven ICPP patients were treated with GnRHa for 4.2 +/- 1.6 yr (range 3-7.9) and observed for 9.9 +/- 2.0 yr (range 4-10.6 yr) after discontinuation of treatment; to estimate the efficacy better, 32 comparable ICPP untreated girls were analyzed. RESULTS: AH was 159.8 +/- 5.3 cm, significantly higher than pretreatment predicted AH (PAH) either for accelerated or for average tables of Bayley and Pinneau. The gain in centimeters between pretreatment PAH and AH was 5.1 +/- 4.5 and 9.5 +/- 4.6 cm, respectively. Hormonal values and ovarian and uterine dimensions, reduced during treatment, increased to normal after 1 yr without therapy. Age of menarche was 13.6 +/- 1.1 yr with an interval of 0.9 +/- 0.4 yr after therapy. Menstrual pattern was normal. Six girls became pregnant and delivered normal offspring. BMI sd score for chronological age increased, but not significantly, before, during, and after therapy. BMD at discontinuation of treatment was significantly lower and increased to control values after gonadal activity resumption. CONCLUSIONS: GnRHa treatment in ICPP is safe for the reproductive system, BMD, and BMI and helpful in reaching AH close to target height; however, the variability of individual responses suggests that one choose more parameters than increment in height, especially in girls with pubertal onset over 8 yr of age.     

PLASMA CALCITONIN AND ACTH RESPONSES TO LYSINE VASOPRESSIN, CALCIUM AND PENTAGASTRIN IN A PATIENT WITH MEDULLARY THYROID CARCINOMA ASSOCIATED WITH CUSHING''S SYNDROME

In a case study of medullary thyroid carcinoma (MTC) associated with Cushing's syndrome, elevated levels of urinary 17-hydroxycorticosteroids, plasma ACTH, cortisol, calcitonin (CT) and somatostatin (GHRIH) were documented. Lysine vasopressin administration further increased the levels of plasma ACTH, cortisol and CT, whereas the administration of calcium and pentagastrin increased only the level of plasma CT. Immunoreactive ACTH, CT and GHRIH were highly concentrated in the tumour tissues. Basal plasma ACTH levels were more progressively increased than plasma CT during the postoperative course when the patient was treated with o,p'-DDD, since the tumour was not completely resected. These findings suggest that the secretion of ACTH and CT from MTC were regulated in a different manner.     

Pesticides interfere with the nongenomic action of a progestogen on meiotic maturation by binding to its plasma membrane receptor on fish oocytes

Although many environmental contaminants disrupt endocrine function by binding to nuclear steroid receptors, it is not known whether they are capable of binding to steroid membrane receptors and interfering with nongenomic actions of steroids. The binding of several organochlorine pesticides to the plasma membrane receptor for the maturation-inducing steroid, 17,20beta,21-trihydroxy-4-pregnen-3-one (20beta-S), in the ovaries of spotted seatrout (Cynoscion nebulosus) was investigated in in vitro competition assays. Kepone and o,p'-DDD were competitive inhibitors of 20beta-S binding and caused concentration-dependent displacement of [3H]-20beta-S from its receptor site over the range of 10(-4) to 10(-6) or 10(-7) M, whereas several other pesticides had lower affinities for the receptor. Interference with the nongenomic actions of 20beta-S on final meiotic maturation of spotted seatrout oocytes (final oocyte maturation, FOM) was examined in an in vitro bioassay. A concentration-dependent inhibition of FOM in response to 20beta-S was observed after 5 min and 12 h exposure to the same range of Kepone and o,p'-DDD concentrations (10(-4) to 10(-6) or 10(-7) M). The close correspondence between competitive binding of the two pesticides to the 20beta-S membrane receptor and their inhibition of 20beta-S induced FOM suggests a mechanism of endocrine disruption mediated by binding to a steroid membrane receptor and antagonism of a nongenomic steroid action.     

Changes in lactate dehydrogenase, LDH isoenzymes, lactate, and pyruvate as a result of feeding low fat diets to healthy men and women.

A study was conducted to evaluate the effects on blood lipids and lipoproteins of feeding 21 healthy volunteers, 40-60 yr old, foods commonly eaten in the United States for two 40-day periods. Activities of lactate dehydrogenase (LDH) and LDH isoenzymes, lactate, and pyruvate were monitored. Results showed that LDH activity was significantly lower in all subjects at the end of the 25% fat-calorie period (period I) than at the beginning of the study, but rose above initial levels at the end of the 35% fat-calorie period (period II). While total LDH fell during period I, relative activity of M type subunits of LDH rose significantly in relation to H type in both sexes. This rise is probably indicative of an increase in glycolytic activity as a consequence of the increased intake of dietary carbohydrate. In period I, lactate and pyruvate decreased significantly in males (pyruvate greater than lactate) but not in females. Values for males returned to near initial levels in period II. The ratio of lactate/pyruvate was elevated in both sexes after period I. The greater change in pyruvate relative to lactate with increased dietary carbohydrate suggests increased Krebs Cycle activity. There was a statistically significant positive correlation between lactate, pyruvate, and serum triglyceride for males after they ate the 25% and 35% fat-calorie diets and for females after they ate the 35% fat-calorie diet, but not between lactate, pyruvate, and serum cholesterol for either sex.