OBJECTIVE

In the present study, the metabolism of steroid hormones has been investigated to determine whether and how xenobiotics like lead (Pb) and polychlorinated biphenyls (PCBs) interfere with steroid hormone biotransformation in humans.

METHODS

Three groups of subjects were tested for concentration of urinary total steroids, <em>17</em>-<em>ketosteroids</em> (n = 5), pregnane derivates (n = 6), <em>17</em>-hydroxycorticosteroids (n = 11) and their sulfonated compounds: 14 workers exposed to lead, with a mean Pb blood concentration (PbB) of 29.21 microg/dl; 15 subjects exposed to PCBs, with a mean PCB blood concentration (PCBB) of 61.69 microg/l; a control group (n = 25).

RESULTS

The urinary concentrations of <em>17</em>-<em>ketosteroids</em> and <em>17</em>-hydroxycorticosteroids were significantly lower in the PCB-exposed groups. There were significantly fewer sulfonated <em>17</em>-hydroxycorticosteroids in the subjects exposed to PCBs as compared to the controls, while the percentage of sulfonated steroids was lower for both <em>17</em>-<em>ketosteroids</em> and <em>17</em>-hydroxycorticosteroids in the PCB-exposed subjects, but only for the <em>17</em>-hydroxycorticosteroids in the group of subjects exposed to Pb (P < 0.05). Pregnane derivate urinary concentrations did not differ between the three groups.

CONCLUSIONS

Our results suggest that PCBs and Pb act on steroid hormone metabolism with different effects and only partially using the same hormone pathways; they may cause changes in endogenous hormone homeostasis and interfere with the xenobiotic phase II of detoxification. PCBs interfere on a larger number of steroids and cause more significant effects than Pb. It is likely that different mechanisms are involved in steroid hormone metabolism interference.

Although the toxicity/biocompatibility of hydroxyapatite nanoparticles (HAPNPs), a prospective nano-biomaterial, is extensively studied, its interaction on the reproductive system following exposure is less exploited. In the present study, male rats were exposed to HAPNPs (300 mg/kg BW) to determine its possible reproductive toxicity. Also, the protective effects of chitosan (CSNPs, 280 mg/kg BW) and/or curcumin (CurNPs, 15 mg/kg BW) nanoparticles against HAPNPs-induced reproductive toxicity were studied. Animals were orally gavage daily with respective doses for 45 consecutive days. The obtained results indicated that HAPNPs caused a significant decrease in sperm count, sperm motility, testosterone hormone, steroidogenic enzymes (<em>17</em>-<em>ketosteroid</em> reductase and <em>17</em>β-hydroxysteroid dehydrogenase), and antioxidant enzymes (glutathione peroxidase, glutathione S-transferase, catalase, and superoxide dismutase) in addition to total antioxidant capacity and reduced glutathione. LH and FSH, abnormal sperm, oxidative stress parameters (thiobarbituric acid-reactive substances (TBARS), nitric oxide (NO), and 8-hydroxy-deoxyguanosine (8-OHdG)), p53, TNFα, and interleukin-6 were significantly increased. The DNA damage was also analyzed by assaying 8-OHdG level which is considered as an indicator of genotoxicity and also suppression of the gene expression of mtTFA, induction of UCP2. Similarly, the histopathological evaluation was also changed following exposure to HAPNPs. The antioxidant activity of CSNPs and CurNPs showed mitigating effect against reproductive deterioration induced by HAPNPs throughout improvements in semen characteristics, sex hormones, inflammatory factors, and antioxidant status. The present study concluded that HAPNPs induced reproductive toxicity and it is important to use nano-antioxidants CSNPs and CurNPs as protective agents.

Keywords: 8-hydroxy-deoxyguanosine; Chitosan nanoparticle; Curcumin nanoparticle; Hydroxyapatite nanoparticles; Mitochondria; Oxidative damage; Reactive oxygen species; Reproductive toxicity; Uncoupling protein; mTFA.

Thirty-one cases of idiopathic hirsutism, characterized biochemically in the basal state by increased levels of urinary 3 alpha-androstane-5 alpha, <em>17</em> beta-diol and normal levels of the main androgens, were studied. In order to determine a possible etiologic heterogeneity of idiopathic hirsutism, pituitary gonadotropin responses to synthetic luteinizing-releasing hormone (LRH) and adrenal steroid responses to adrenocorticotropic hormone (ACTH) stimulation were evaluated and the results were compared to those in six normal women. On the basis of the results obtained in each hirsute patient after LRH and ACTH tests, two groups were identified. The majority, 23 of 31 hirsute patients (group I), had results similar to those in the control group. In the other eight patients (group II), biologic abnormalities were disclosed and suggested a partial adrenal 11 beta-hydroxylase defect in two patients, an incomplete form of adrenal 3 beta-ol deficiency in one patient, an adrenal hyperreactivity without evident cause in two patients, and polycystic ovary syndrome in association with an adrenal hyperreactivity in three patients. As a group, the eight patients showed ACTH-stimulated increments in testosterone, delta 4-androstenedione, dehydroepiandrosterone, and <em>17</em>-<em>ketosteroids</em> that were significantly greater (p less than 0.01) than the mean responses in the control group. The conclusion is that some women who previously were designated as having "idiopathic" hirsutism had an adrenal and/or ovarian component to their hyperandrogenism which could be shown only by appropriate dynamic tests.

In order to verify the relationship between insulin resistance and hyperandrogenism in Polycystic ovary disease (PCOD), circulating levels of insulin in response to oral glucose tolerance test (OGTT) were assessed in 23 PCOD patients and 10 matched control subjects without obesity, acanthosis nigricans and impaired glucose tolerance. In PCOD patients serum total testosterone (T), dehydroepiandrosterone sulfate (DHEA-S), LH and LH/FSH ratio were significantly higher than in control subjects; whereas urinary <em>17</em>-<em>ketosteroids</em> (<em>17</em>-KS) and glycemic response to OGTT were not different. PCOD patients were clearly hyperinsulinemic before and during OGTT compared to the control group: mean +/- SD basal insulin (Io) (23.4 +/- 10.3 vs 11.3 +/- 4.6 microU/ml, p less than 0.001) and the sums of insulin levels (sigma I) during OGTT (341.4 +/- 148.9 vs 162.2 +/- 56 microU/ml, p less than 0.001). In the two groups serum T, but not DHEA-S, LH, urinary <em>17</em>-KS and the degree of obesity, was strongly associated with Io (r = 0.458, p less than 0.01) and sigma I (r = 0.419, p less than 0.02), as well as with insulin resistance as assessed by basal (r = 0.425, p less than 0.02) and postglucose challenge (r = 0.384, p less than 0.05) insulin to glucose ratio. These results confirm that the hyperinsulinism and insulin resistance in PCOD is not related to obesity and suggest that the hyperandrogenism may be partially responsible of the observed imbalance in glucose-insulin homeostasis.

A nationwide study of the steroid excretion patterns in postmenopausal Israeli migrant women demonstrated differences between high- and low-risk groups for breast cancer in the following variables: age at first parturition, number of pregnancies, number of live births, height, and weight. The direction of the differnces was in line with those observed for breast cancer patients. The groups also differed in the exretion of estriol, <em>17</em>-<em>ketosteroids</em>, and allotetrahydrocortisol. Multiple regression analysis revealed that the exretion of estriol was significantly lower in population groups in whom breast cancer incidence was high. Possibly this trend--which has also been observed in adolescent and premenopausal women--reflected environmental influences on peripheral estrogen metabolism.

Serum <em>17</em>alpha-hydroxyprogesterone (<em>17</em> OH-P) was measured by a specific radioimmunoassay technique combined with thin-layer chromatography. Normal values for children are less than 1.1 microgram/1 (less than 3.3 nmol/l)--corresponding to values found in the literature. In congenital adrenal hyperplasia (CAH) values up to several hundred microgram/l are found. The values rise after ACTH stimulation and are suppressed by decadrone or cortisone treatment. The rise in <em>17</em> <em>ketosteroids</em> and pregnanetriol in untreated CAH is relatively smaller (15--25 fold). This clinical sensitivity of <em>17</em> OH-P is thus valuable for the diagnosis of CAH (21 hydroxylase deficiency). Furthermore it is easier to take a blood sample than to collect urine for 24 hours. The usefulness in therapeutic monitoring is being studied.

The clinical symptomatology and diagnostic procedures of pseudohypoaldosteronism in an 8 days old male newborn infant are described. The course of the disease was initially characterized by failure to thrive, renal salt loss, hyponatremia and hyperkalemia. Daily treatment with 3 g sodium chloride improved symptoms. Hydrocortisone and desoxycortiscosteronacetate were without any effect. Urinary aldosterone excretion was increased 10 to 20 times of normal. <em>17</em> <em>ketosteroid</em> and pregananetriol were normal. The infant died of ulcerative enterocolitis at the age of 1 1/2 years. Beside the first description of the disease by Cheek et al. (1958) 13 further publications have been collected from the literature. Symptoms at the beginning, sex, serum electrolytes, aldosterone excretion, somatic development, observation period, treatment and duration of therapy are compared with the presented case report.

A woman with periodic catatonia had a 600-day metabolic study. The results were analyzed by harmonic analysis. Her periodic stupors showed a regular 36-day rhythm apparently related to a 24-day menstrual cycle; but the rhythm persisted when menstrual function was blocked by continuous Enovid (norethynodrel + mestranol) administration. During the menstrual block, weight, sodium balance, magnesium and <em>17</em>-<em>ketosteroid</em> (<em>17</em>-KS) excretion gave indications of 12- and 36-day fluctuations. Further studies on steriod excretion indicated that similar fuctuations in <em>17</em>-KS output occurred when the patient was menstruating normally. The peaks of the 12-day cycle coincided with menses and the mid-menstrual phase; while the peak of the 36-day cycle coincided with the onset of stupor. <em>17</em>-hydroxycorticosteroid (<em>17</em>-OHCS) excretion had a 36-day cycle which lagged 4 days behind the 36-day <em>17</em>-KS cycle. There were no indications of a 12-day <em>17</em>-OHCS cycle. In the discussion it is suggested that the <em>17</em>-KS fluctuations may partly reflect gonadotrophin activity rather than being exclusively due to ACTH. It is noted that Enovid may block only LH activity not total gonadotrophins. It is speculated that there may be a relationship between gonadotrophin activity and the psychic disturbance.