Altered Hormonal Milieu Research Articles

Relationship of obesity, Androgen receptor genotypes and biochemical failure after radical prostatectomy

Obesity and androgen metabolism have been implicated in the progression of prostate cancer. Obesity has been associated with increased risk for advanced disease and biochemical failure after treatment. This association may be the result of changes in androgen metabolism that occur with obesity and are mediated by the androgen receptor (AR). To evaluate the effects of obesity and AR polymorphisms on biochemical failure, we conducted a study of 536 Caucasian prostate cancer cases. We determined the relationship between time to biochemical failure and obesity stratified by short and long AR-CAG and AR-GGN repeat sequence. The AR repeat groups were dichotomized at the median number of repeats for each polymorphism. An association was found for obesity in the short CAG group (HR = 3.45, 95% CI = 1.00-11.96). Among obese patients diagnosed with localized disease (T1/T2), the risk of biochemical failure was significantly higher (HR = 7.05, 95% CI = 1.55-32.06). No difference was observed for high stage (T3/T4) obese patients. Additionally, no differences in biochemical failure were observed in obese and non-obese men grouped by number of AR-GGN repeats. Obesity is significantly associated with increased risk of biochemical failure in men with the high-risk short CAG sequence on the AR gene. This effect is not observed in men with long CAG repeats. Therefore, it appears that the relationship between biochemical failure and obesity may be modified by the AR-CAG repeat pattern. The short AR-CAG genotype may be more responsive to an altered hormonal milieu created by obesity.

Novel insight into glucagon receptor action: lessons from knockout and transgenic mouse models.

Using knockout and transgenic technology, genetically modified animal models allowed us to understand the role of glucagon signalling in metabolism. Mice with a global deletion of the glucagon receptor gene (Gcgr) were designed using gene targeting. The phenotype of Gcgr(-/-) mouse provided important clues about the role of Gcgr in foetal growth, pancreatic development and glucose and lipid homeostasis. The lack of Gcgr activation was associated with: (i) hypoglycaemic pregnancies, poor foetal growth and increased foetal-neonatal demise; (ii) altered cytoarchitecture of pancreatic islets; (iii) altered glucose, lipid and hormonal milieu; (iv) reduced gastric emptying; (v) altered body composition and protection from diet-induced obesity; (vi) altered energy state; (vii) impaired hepatocyte survival; (viii) altered metabolic response to prolonged fasting and exercise and (ix) prevented development of diabetes in insulin-deficient mice. In contrast, mice overexpressing the Gcgr on pancreatic β-cells displayed an increase insulin secretion, pancreatic insulin content and β-cell mass, and partially protected against hyperglycaemia and impaired glucose tolerance when fed a high-fat diet. These findings suggest that glucagon signalling plays a significant role in the regulation of glucose and lipid homeostasis. Treatment options designed to block Gcgr activation may have negative implications in the treatment of diabetes.

Disseminated Peritoneal Leiyomyomatosis in an 18-Year-Old Girl

Disseminated peritoneal leiomyomatosis (DPL) is a rare hormone-dependent disease entity occurring primarily in women of reproductive age group subjected to an altered hormonal milieu. The lesion is characterized by numerous subperitoneal nodules of benign smooth muscle proliferations which usually mimic the macroscopic appearance of metastatic malignancy. In 70% of cases, the underlying cause of hormonal alteration is pregnancy and in the remaining cases, the causes are oral contraceptives or hormone-secreting tumors. This indicates that endocrine factors are of importance in the development of this condition. This is an unusual case, hitherto unreported, of DPL with multiple uterine leiomyoma, occurring in a 18-year-old girl, who had previously undergone several laparoscopic surgical resections of uterine leiyomyomas. Her disease was unrelated to pregnancy or to any other obvious sources of hormonal elevation.

Cancer risk in mothers of men operated for undescended testis.

BackgroundUndescended testis, or cryptorchidism, occurs in 2–5% of boys born at term, and by 12 months of age about 1% of all boys have manifest cryptorchidism. Several hormonal substances control this process and disruption of the foetal sex-hormones balance is a potential cause of undescended testis, however, to a great extent the aetiology of cryptorchidism is unclear.MethodologyTo study risk factors involved in the aetiology of undescended testis, we assessed cancer risk in 15,885 mothers of men operated for undescended testis in Sweden. Women were followed-up for a median period of 23 years during which 811 first primary malignancies occurred. Their cancer incidence was compared with that in the general population estimating standardized incidence ratio (SIR) and corresponding 95% confidence interval (CI).Principal FindingsThe overall cancer risk experienced by the mothers of cryptorchid men did not differ significantly from that of the general population (SIR = 0.94; 95% C.I. = 0.88–1.01). Specifically, there was a reduction in ovarian cancer risk (SIR = 0.72; 95% C.I. = 0.51–0.99), while the risk of lung (SIR = 1.38 95% C.I. 1.03–1.81) and biliary tract/liver cancer (SIR: 1.76, 95% CI: 1.03–2.82) were increased.ConclusionsAlthough we cannot rule out the role of chance, our data suggest a positive association between undescended testis and maternal lung cancer and a negative association with ovarian cancer, where the first may be partly attributable to smoking and the second to an altered hormonal milieu during pregnancy and thus both exposures may be risk factors for cryptorchidism.

Research Resource: Estrogen-Driven Prolactin-Mediated Gene-Expression Networks in Hormone-Induced Prostatic Intraepithelial Neoplasia

Cotreatment with testosterone (T) and 17β-estradiol (E2) is an established regimen for inducing of prostatic intraepithelial neoplasia (PIN) and prostate cancer in rodent models. We previously used the pure antiestrogen ICI 182,780 (ICI) and bromocriptine, a dopamine receptor agonist, to inhibit PIN induction and systemic hyperprolactinemia in Noble rats and found that the carcinogenic action of T+E2 is mediated directly by the effects of E2 on the prostate and/or indirectly via E2-induced hyperprolactinemia. In this study, we delineate the specific action(s) of E2 and prolactin (PRL) in early prostate carcinogenesis by an integrated approach combining global transcription profiling, gene ontology, and gene-network mapping. We identified 2504 differentially expressed genes in the T+E2-treated lateral prostate. The changes in expression of a subset of 1990 genes (∼80%) were blocked upon cotreatment with ICI and bromocriptine, respectively, whereas those of 262 genes (∼10%) were blocked only by treatment with ICI, suggesting that E2-induced pituitary PRL is the primary mediator of the prostatic transcriptional response to the altered hormone milieu. Bioinformatics analyses identified hormone-responsive gene networks involved in immune responses, stromal tissue remodeling, and the ERK pathway. In particular, our data suggest that IL-1β may mediate, at least in part, hormone-induced changes in gene expression during PIN formation. Together, these data highlight the importance of pituitary PRL in estrogen-induced prostate tumorigenesis. The identification of both E2- and pituitary PRL-responsive genes provides a comprehensive resource for future investigations of the complex mechanisms by which changes in the endocrine milieu contribute to prostate carcinogenesis in vivo.

Subcellular Localization of Cyclic AMP-Responsive Element Binding Protein-Regulated Transcription Coactivator 2 Provides a Link between Obesity and Breast Cancer in Postmenopausal Women

Epidemiologic evidence supports a correlation between obesity and breast cancer in women. AMP-activated protein kinase plays an important role in energy homeostasis and inhibits the actions of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 (CRTC2). In postmenopausal women, the cyclic AMP-responsive element binding protein-dependent regulation of aromatase is a determinant of breast tumor formation through local production of estrogens. The present work aimed to examine the effect of adipokines on aromatase expression and identify additional mechanisms by which prostaglandin E(2) causes increased aromatase expression in human breast adipose stromal cells. Treatment of human adipose stromal cells with forskolin and phorbol 12-myristate 13-acetate (PMA), to mimic prostaglandin E(2), resulted in nuclear translocation of CRTC2. Aromatase promoter II (PII) activity assays showed that CRTC2 in addition to forskolin/PMA treatment significantly increased PII-induced activity. CRTC2 binding to PII was examined by chromatin immunoprecipitation, and forskolin/PMA treatment was associated with increased binding to PII. Treatment of human adipose stromal cells with leptin significantly up-regulated aromatase expression associated with nuclear translocation of CRTC2 and increased binding of CRTC2 to PII. Adiponectin treatment significantly decreased forskolin/PMA-stimulated aromatase expression, consistent with the decreased nuclear translocation of CRTC2 and the decreased binding of CRTC2 to PII. The expression and activity of the AMP-activated protein kinase LKB1 was examined and found to be significantly decreased following either forskolin/PMA or leptin treatment. In contrast, adiponectin significantly increased LKB1 expression and activity. In conclusion, the regulation of aromatase by CRTC2, in response to the altered hormonal milieu associated with menopause and obesity, provides a critical link between obesity and breast cancer.

Pregnancy and its role in breast cancer

Early full-term pregnancy is the only recognized factor able to prevent breast cancer. There are several hypotheses to explain the mechanisms of this protection, namely an altered hormonal milieu, a differentiation process or a switch in stem cell properties. To explore them, authors have been using animal models, mainly in rodents. Hormonal administration with estrogen and progesterone was the most widely used process to mimic the mammary changes during pregnancy. We have recently proposed that this enigmatic protective role of a full-term birth in breast cancer is carried out by tumor inhibition mediated by differentiated mammary epithelial cells. This explanation may give a new perspective of breast cancer prevention and treatment.

Body mass index (BMI) and serum parathyroid hormone (sPTH) influence cortical bone in premenopausal women

Continuous endogenous sPTH excess has been shown to have catabolic effects on trabecular and cortical bone in normal‐weight women. In this study we examined the relationship between sPTH levels and BMI on cortical and trabecular volumetric bone mineral density (vBMD) and geometry in 87 normocalcemic obese and non‐obese women. Measurements were made by peripheral quantitative computed tomography at 4% and 38% from the distal tibia. In 43 premenopausal women, we used the median to categorize sPTH (pg/mL) as higher (70 ± 24) and lower (29 ± 4), and categorized BMI (kg/m2) into obese (39 ± 9) and non‐obese (26.5 ± 1.8). A similar analysis was performed for a postmenopausal population. Not surprisingly, we found that obesity increased cortical vBMD and content (BMC), geometric properties (area, thickness, circumference), polar moment of inertia and the stress:strain index in all women (P < 0.05), and also increased trabecular vBMD and BMC (P < 0.02) in the premenopausal women. We found an interaction (2‐way ANOVA) between BMI and sPTH for cortical BMC and geometric variables (p < 0.05) in the premenopausal women. Hence, the positive influence of BMI on cortical bone geometric properties is dependent on higher sPTH in the younger women. These findings suggest that the altered hormonal milieu associated with obesity is an important determinant in modulating the effects of excess weight on the skeleton.

PROTEIN EXPRESSION OF STEROIDOGENIC ENZYMES IN OVARIAN TUMORS OF THE DOMESTIC HEN

Advances in understanding the development of ovarian cancer may help in the identification of screening markers to detect early stages of the disease. Epidemiological data indicate that pregnancy and breast feeding are protective for ovarian cancer. The protective effects of reduced ovulations in these physiological states compared to the accompanying altered hormonal milieu, have been difficult to separate experimentally. Sex steroids have been implicated in ovarian cancer with evidence indicating that progesterone (P) inhibits the growth of tumor cells and that estrogen (E) promotes proliferation. Studies also suggest that ovarian tumors may be the site of synthesis of sex steroids. Like the human, the domestic hen spontaneously develops ovarian cancer in an age-related manner. We have previously found that 100% of ovarian tumors in the hen express ovalbumin, the major protein normally synthesized in the oviduct under the regulation of E. We have also demonstrated that hen tumors are positive for P and E receptors. In the present study, we examined the expression of 3-beta-hydroxysteroid dehydrogenase (3-beta- HSD) and aromatase in normal ovarian tissue and in ovarian tumors from the domestic hen. Tissues were fixed in formalin, embedded in paraffin, sectioned and mounted on glass slides. They were subsequently deparaffinized, rehydrated and processed using either of 2 antigen retrieval methods: boiling in citrate buffer for 20 minutes (for 3-beta-HSD antibody) or incubating in pronase for 30 minutes at 37° C (aromatase antibody). Primary antibody was applied for 16 hrs at 5° C and secondary antibody for 1 hr at 37° C. Tissues were examined with a Nikon E600 microscope under epifluorescence using fluorescein isothiocyanate excitation and barrier filter sets. Primary antibodies were rabbit polyclonal antiserum to recombinant human 3-beta-HSD diluted 1:1000, rabbit polyclonal antiserum to aromatase (Abcam, ab18995) used at a concentration of 20 μg/ml and IgG rabbit control serum (negative control). Secondary antibody was Alexa Fluor 488 goat anti-rabbit IgG conjugate (1.0 μg/ml; Invitrogen Molecular Probes). Ten of 14 (71%) ovarian tumors were positive for 3- beta-HSD protein with expression localized to the tubular/glandular areas of the tumors. In addition, expression was often observed in the theca or granulosa of normal follicles associated with the ovarian tumors. Follicles of normal ovaries (n=4) were positive for 3-beta-HSD and IgG controls (n=4) were negative. No ovarian tumors (n=10) were positive for aromatase in the tubular/glandular areas, however, 2 of the tumors had normal appearing follicles which were positive. Follicles of normal ovaries (n=4) were positive for aromatase and IgG controls (n=2) were negative. Our results indicate that 3-beta-HSD enzyme is present in the tubular/glandular areas of ovarian tumors and suggest that P or androgens could be synthesized in the tumors of the hen. Furthermore, aromatase activity is absent in the ovarian tumors of the hen with the exception of normal follicles and therefore, it is unlikely that E is being synthesized by the neoplastic cells. (poster)

Hormonal Effects in Infants Conceived by Assisted Reproductive Technology

The purpose of this report is to describe 7 infants conceived by assisted reproductive technology (ART) who presented with breast development and/or pubic hair. The clinical presentation in these infants raises awareness that an altered intrauterine hormonal milieu may impact the fetal and infant stages of children conceived by ART. Between May 2001 and April 2004, 7 children between the ages of 5 and 21 months conceived by ART were referred by their pediatricians to the Division of Pediatric Endocrinology at the New York University School of Medicine for evaluation of possible precocious puberty. Patients were evaluated for the possibility of centrally mediated precocious puberty and pseudoprecocious puberty, with a possible ovarian or adrenal origin. Endocrine evaluation in all patients indicated sex-steroid and hormone levels in the prepubertal range; pelvic sonography confirmed prepubertal ovaries with unstimulated uteri. Clinical follow-up of our patients thus far has not revealed progression of breast development, pubarche, or elevation in sex steroids. It is well established that the developing endocrine system in the fetus and maturation of endocrine-control systems are influenced by hormone concentrations in the fetus. Whether ART alters the intrauterine hormonal milieu for the growing fetus conceived by ART is as yet unknown and is an area of ongoing investigation. Patients conceived through ART, including our patients who presented with hormonal manifestations, will need to be monitored throughout childhood and into adolescence and adulthood to determine if any perturbation exists on the timing of puberty and later fertility.

Cellular distribution of phosphofructokinase activity and implications to metabolic regulation in human breast cancer

Neoplastic cells generally present profound changes in glucose metabolism. The mechanisms underlying such process are numerous and all may involve altered cellular hormonal responses. Here we report the first evidence that cellular location of phosphofructokinase activity in human breast cancer tissues is different from the one observed in control tissues and that this phenomenon may be involved in the increased glycolytic flux observed in those cells. Through co-sedimentation techniques, we observed that 60% of phosphofructokinase activity in neoplastic tissues is located in an actin-enriched fraction, against 36% in control tissues. Additionally, metastatic tumor tissues presented a two fold increase in this particulate activity when compared to non-metastatic tumor samples. We propose that the alteration in cellular distribution of phosphofructokinase activity in human breast cancer tissues is a mechanism associated to the process of cell transformation and may be a consequence of the altered hormonal milieu observed in several types of cancer.

Food Restriction Differentially Affects Pituitary Hormone mRNAs throughout the Adult Life Span of Male F344 Rats

Because neuroendocrine mechanisms may contribute to the antiaging effects of food restriction (FR), we measured the effect of FR on mRNAs encoding anterior pituitary (AP) tropic hormones. Slot blots or RNase protection assays were done on AP RNA from 3-, 6-, 12-, 18- and 24-mo-old male F344 rats consuming food ad libitum (AL) or food restricted (FR; to 60% of AL food intake) from 6 wk. Both AL and FR rats gained body weight during the study (P < 0.05), but FR rats weighed ∼40% less (P < 0.0001). Messenger RNA levels were expressed in two ways, i.e., per total AP and per microgram total AP RNA. Proopiomelanocortin (POMC) mRNA/μg RNA was higher (P < 0.0005) in FR than in AL rats at all ages. Thyroid-stimulating hormone (TSH) β mRNA declined with age (P < 0.05) in AL but not FR rats and was reduced by FR up to 12 mo (P < 0.01). Growth hormone (GH) mRNA/μg RNA declined with age (P < 0.05) in AL but not FR rats, and total GH mRNA in the AP was reduced by FR at early ages (P < 0.05). FR reduced prolactin (PRL) mRNA and its age-related increase (P < 0.0005). Levels of luteinizing hormone (LH) β and follicle-stimulating hormone (FSH) β mRNAs did not differ between AL and FR rats until 12 mo, but thereafter rose in FR (LH β mRNA; P < 0.01, FSH β mRNA; P < 0.05). Many of these changes in gene expression corroborate previously reported hormonal changes in FR rodents and mutant mice with extended life spans, and thus provide further support for the hypothesis that an altered hormonal milieu contributes to the antiaging effects of food restriction.

Enteral versus parenteral nutrition in the critically ill

P roviding nutritional support for critically ill patients has become easier over the past decade with the advent of total parenteral nutrition and then enteral nutrition. Traditionally, patients who are critically ill are septic with systemic evidence of infection including tachypnea, tachycardia, and hypoand hyperthermia. This may lead to sepsis syndrome and subsequent multisystem organ failure. Characteristic changes in the septic patient include an altered hormonal milieu, hypermetabolism, an increase in nitrogen excretion, altered glucose, fat, and amino-acid metabolism, depletion of energy and protein, and acute anorexia. This accounts for 10–50% of deaths in the intensive-care unit.1 The goals of nutritional support in a critically ill patient include detecting and correcting any preexisting malnutrition, preventing progressive protein-calorie malnutrition, optimizing the patient’s metabolic state, and decreasing the morbidity, mortality, and duration of recovery. The decision between enteral and parenteral nutritional support is not straightforward.

Effect of glucagon on protein synthesis in human rectal cancer in situ.

The purpose of this study was to determine the effect of glucagon or placebo on the rate of tumor fractional protein synthesis in situ in patients with localized rectal cancer who were not malnourished, demonstrated normal glucagon concentrations, and could therefore be used as a model to study the glucagon effect. Cancer cachexia is associated with an increased concentration of counterregulatory hormones, including glucagon. This altered hormonal milieu may not only contribute to malnutrition, but also promote tumor growth, because previous experimental work suggests that glucagon can cause human colorectal tumor cells to proliferate. Corresponding mechanisms in vivo have, thus far, not been investigated. Advanced mass spectrometry techniques (capillary gas chromatography [GC]/combustion isotope ratio mass spectrometry [IRMS]) were used to determine directly the incorporation rate of 1-[13C]-leucine into tissue protein. Because GC/IRMS requires only a small sample volume, three consecutive endoscopic biopsies could be obtained from the same tumor to determine isotopic enrichments at baseline, after a 4-hour glucagon infusion (3 ng/kg/min), or after placebo. In patients with localized rectal cancer, glucagon caused the tumor fractional protein synthetic rate to double (2.25+/-0.49 %/hr, p < 0.05 vs. 1.16+/-0.30 basal). In contrast, tumor protein synthesis declined over time in controls (placebo) (0.67+/-0.09 %/hr, p < 0.05 vs. 1.11+/-0.16 basal). Tumor protein synthesis and growth can be stimulated by glucagon in situ. Therefore, elevated glucagon concentrations in cachectic cancer patients should be considered detrimental and attempts made to prevent this specific response of the body to the malignant disease.

Fertility and Contraception in End-Stage Renal Disease

The hormonal aberrations that occur with end-stage renal disease (ESRD) are presented in this review in relation to fertility and conception among women on dialysis. The imbalance in gonadotropin production in dialysis-dependent men and women is characterized by elevations in luteinizing hormone (LH). In women dialysis patients, the normal estradiol-stimulated LH surge does not occur, resulting in anovulation. In men dialysis patients spermatogenesis is impaired, and low testosterone levels cause elevated LH. Infertility in those with ESRD is a culmination of many factors, including impotence and loss of libido, anovulation, and an altered hormonal milieu. Despite these inhibitors of conception, women on dialysis can conceive; pregnancy has been reported in 1% to 7% of women on dialysis in survey studies. The influence of dialysis mode (hemodialysis v peritoneal dialysis), recombinant human erythropoietin (EPO), and dialysis adequacy on the likelihood of conception among patients of either sex on dialysis is unknown. Reduced sexual activity and interest has consistently been reported in the ESRD population. The reasons for this are complex and likely involve the effects of comorbid illnesses, overall health status, body image factors, and hormonal alterations. Nephrologists rarely discuss conception and contraception with their women dialysis patients. Greater attention to these issues is needed.

Follicular and luteal phase hormonal responses to low-volume resistive exercise

The purpose of the study was to 1) determine the effects of a low-volume resistive exercise protocol on serum concentrations of estradiol (E2), progesterone (P4), growth hormone (GH), testosterone (T), and androstenedione (AN) and 2) ascertain whether the endocrine responses are affected by the phase of the menstrual cycle. Eleven untrained, healthy women were assigned to either an early follicular or luteal testing group. The subjects completed three sets of bench press, lat-pull, leg extension, and leg curl exercises at a 10 repetition maximum load on fixed machines with 2-min of rest between sets. Blood samples were collected through an indwelling cannula before, during, and after the exercise. Area-under-the-response-curve (AUC) data demonstrated that E2 concentrations were significantly elevated in both follicular and luteal phases with a greater response in the luteal phase. Moreover, data suggest there is a luteal phase-induced increase in GH and AN in response to the low-volume resistive exercise; however, P4 and T concentrations in untrained women are not increased by low-volume resistive exercise with 2-min rest periods, nor does the altered hormonal milieu produced by the phase of the menstrual cycle affect these hormonal responses.

Beta-human chorionic gonadotropin, progesterone, and aqueous dynamics during pregnancy.

To determine whether the altered hormonal milieu of pregnancy is associated with changes in the dynamics of aqueous humor formation and drainage. Nineteen women were studied during each trimester of a single pregnancy and post partum. Measures of aqueous dynamics included intraocular pressure, aqueous flow, facility of outflow, aqueous flare, and corneal thickness. Pregnancy was associated with relatively lower intraocular pressure, reduced aqueous flare, increased corneal thickness, and increased aqueous outflow facility. Aqueous flow was unchanged. The progesterone level increased during pregnancy and decreased during the postpartum period. The beta-human chorionic gonadotropin level was highest during the first trimester. The progesterone level, but not the beta-human chorionic gonadotropin level, was correlated with intraocular pressure, aqueous flare, and corneal thickness. The change in aqueous outflow facility that accompanied pregnancy could not be correlated directly to changes in beta-human chorionic gonadotropin or progesterone concentrations. Aqueous flow remains constant during and after pregnancy, but intraocular pressure decreases during pregnancy due to an increase in the outflow facility. The changes in aqueous dynamics are consistent with the hypothesis that excess progesterone during pregnancy blocks the ocular hypertensive effect of endogenous corticosteroids. However, we were unable to find a statistically significant correlation when a direct comparison between the observed changes in outflow facility and the observed changes in the progesterone level was made, perhaps because of intersubject variability of these changes. The changes in intraocular pressure and outflow facility could have been due to one of many other changes in pregnancy that were not measured.

Lipoprotein-cholesterol levels in infertile women with luteal phase deficiency

To determine if reductions in plasma progesterone (P) secretion seen in luteal phase deficiency (LPD) might be because of reduced availability of circulating low-density lipoprotein (LDL) or high-density lipoprotein (HDL), known substrates for corpus luteum P synthesis. We measured plasma lipoproteins in the luteal phase of the menstrual cycle in 39 infertile women. These women were divided into two groups on the basis of endometrial biopsies; the LPD group had biopsies that were greater than or equal to 3 days out-of-phase. All participants were recruited from the Reproductive Endocrinology and Infertility Clinic at the University of Washington, an institutional tertiary care center. Eighteen women had in-phase and 21 had out-of-phase LPD biopsies. Lipoprotein levels were obtained in a fasted state on the day of the luteal phase on which the biopsy was performed. No difference in covariates that affect lipoprotein levels such as obesity, age, and alcohol use were observed between the two groups. No significant differences between groups were found for triglycerides, total cholesterol, very low density lipoprotein, LDL, HDL, HDL2, and HDL3 concentrations. However, LPD was associated with a reduction in the extent to which: age and obesity are associated with higher triglycerides; obesity is associated with a lower HDL2; and alcohol is associated with a higher HDL3-cholesterol. Lipoproteins on average are not different in LPD, suggesting reasons other than a deficient plasma lipoprotein cholesterol source as the explanation for decreased P secretion. A lesser interaction between LDL or HDL and obesity, age, and alcohol in LPD could signify an influence of the altered hormonal milieu of LPD on the way lipoproteins interact with covariates and could lead to differences in lipoproteins between normal and LPD subjects at the extremes of the lipoprotein distribution.

Plasma Protein and Hormone Profiles Associated with Autoimmune Oophoritis and Ovarian Tumorigenesis in Neonatally Thymectomized Mice

Interactions between the immune and endocrine systems may have an important role in ovarian tumorigenesis. Neonatal thymectomy at 3 days of age (Tx-3) in (C3H/HeMs x 129/J)F1 (C31) female mice results in an autoimmune ovarian dysgenesis then subsequent tumor formation. At 3 months of age the histology of the ovaries showed that approximately 60% of the Tx-3 mice (Tx-3 DO) had completely lost their oocytes and follicles so that a preponderance of interstitial-like cells remained. The remainder of the Tx-3 mice had atypical ovaries (Tx-3 AO). The vaginal cytology showed that both groups of Tx-3 mice became acyclic at an early age compared to the intact mice. Around 12 months of age, a high percentage of the dysgenic ovaries developed trabecular tumors. Plasma protein-related indicators of systemic inflammatory responses showed little change during the course of the autoimmune oophoritis or ovarian tumorigenesis. Levels of estradiol 17 beta (E2) and testosterone (T) did not vary in the Tx-3 mice compared to those of the intact mice through 21 months of age but progesterone levels were lower during the exacerbation of the autoimmune oophoritis and tumor development. By 24 months of age levels of P increased while E2 decreased. Apparently, the premature reproductive failure in these mice at a young-adult stage results from the early loss of the oocytes by the localized autoimmune insult to the ovaries. The autoimmune oophoritis may then be the primary trigger for the subsequent ovarian tumor formation and the tumors succeed in association with the altered hormonal milieu.

Central hypogonadism in burned men.

Serum samples were obtained from 30 burned men at different times up to the fourth month after injury. Mean concentrations of estradiol (E2) were elevated above those for healthy control subjects. Mean serum total testosterone (T), sex hormone-binding globulin (SHBG), bioassayable luteinizing hormone (LH), thyroxine (T4), triiodothyronine (T3) and their free indices (FT4I and FT3I) were depressed below those of controls during the first postburn week. Mean values for T and LH were progressively higher in samples taken from later time periods but remained depressed. Mean SHBG and thyroid hormones rose and were not significantly different from control values during later periods of the study. Calculated non-SHBG-bound T (NSBT) was below normal in each time period. The close correlation of SHBG values with those of T3 and FT3I in the patients suggests that SHBG responds to the altered thyroid hormone milieu of burn injury. It is postulated that elevated serum E2 perhaps from adrenal precursors promotes an alteration of hypothalamic function resulting in a markedly reduced secretion of bioactive LH and diminished Leydig cell function.