Critical illness and low testosterone: effects of human serum on testosterone transport into rat brain and liver.
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Acute Disease↗
Biomedical subjects
H L Judd
Publications and source records attributed to H L Judd.
HLA genotyping in family members and patients with familial polycystic ovarian disease.
To determine whether the familial occurrence of polycystic ovarian disease (PCO) is related to the major histocompatibility complex (HLA), four families in whom at least two siblings had clinical evidence of disease were examined. The diagnosis of PCO was confirmed by increased serum testosterone, androstenedione, and LH levels compared to those in normal women. Elevated concentrations of dehydroepiandrosterone sulfate indicated excess adrenal androgen secretion. The result of HLA genotyping in the families studied demonstrate that PCO does not exhibit linkage to the HLA system.
Androgens↗
Steroid secretion in polycystic ovarian disease after ovarian suppression by a long-acting gonadotropin-releasing hormone agonist.
The principal glandular source of increased serum androgens in polycystic ovarian disease (PCO) is controversial), since complete separation of ovarian from adrenal function has not been achieved. The purpose of this study was to determine whether a long-acting GnRH agonist could be used to selectively inhibit ovarian steroid secretion in PCO and ovulatory women. Each of five typical PCO patients and six ovulatory subjects on day 2 of their menstrual cycles received D-Trp6-Pro9-NEt-LHRH (GnRH-a; 100 micrograms) for 28 consecutive days. Their results were compared to basal serum hormone values in eight oophorectomized women. In response to GnRH-a, PCO and normal subjects exhibited sharp and sustained rises of LH and gradual decreases in FSH. These levels were clearly less than basal levels seen in oophorectomized women. Episodic LH release was significantly attenuated in both groups at the end of GnRH-a treatment. After the administration of agonist, serum estradiol (E2), estrone (E1), androstenedione (A), and testosterone (T) were suppressed to castrate levels in both groups. The decrements of E2 and E1 in PCO were gradual and continuous compared to initial dramatic rises, which reached peaks at 14 days, and subsequent abrupt falls in the ovulatory controls. Serum A and T declined steadily in both groups. Basal serum dehydroepiandrosterone and dehydroepiandrosterone sulfate, but not cortisol, levels were elevated in PCO subjects. The 24-h secretion patterns and responses to ACTH of these hormones in PCO and ovulatory subjects were unaltered by GnRH-a administration. These data demonstrate that 1) in PCO subjects, GnRH-a induced complete suppression of ovarian steroid secretion, as circulating levels at the end of treatment were comparable to those seen in our oophorectomy subjects; 2) elevated A and T levels in PCO patients were derived primarily from the ovary; and 3) adrenal steroid secretion was unaltered by GnRH-a in both PCO and normal women.
Adrenal Cortex Hormones↗
The effect of membrane permeability and binding by human serum proteins on sex steroid influx into the uterus.
To determine the effect of such factors as capillary membrane permeability, plasma protein binding, and capillary transit time on the availability of sex steroids to the uterus, the unidirectional influxes of 3H-labeled steroids from the circulation into the uterus were measured in vivo in anesthetized rats using a tissue-sampling, single injection technique. When dihydrotestosterone (DHT), estradiol (E2), and progesterone (P) were injected with Ringer's solution, the tissue extraction was in excess of 80%; hence, membrane permeability did not play a limiting role. With the more polar steroids, corticosterone and cortisol, uterine extraction was less than 40%. Significant inhibition of tissue extraction of DHT and E2, but not P, occurred with the addition of 4% albumin to the injection solution. Human sera containing increasing concentrations of sex hormone-binding globulin demonstrated inhibition of extraction of DHT and E2. Human sera also inhibited P extraction, presumably secondary to the presence of cortisol-binding globulin and orosomucoid. Large concentrations of unlabeled DHT, E2, and P in the injection solutions did not result in competitive inhibition of labeled steroid extraction. Thus, there is no evidence for a carrier mechanism mediating steroid transport into the uterus. When tissue extraction of E2 from Ringer's solution was compared in liver, brain, and uterus, no difference of tissue permeability could be found. Liver consistently had higher tissue E2 extraction than brain or uterus in the presence of human sera. The results are compatible with the influx of albumin-bound E2 into all three tissues and the influx of sex hormone-binding globulin-bound E2 into the liver.
Animals↗
Biological effects of various doses of vaginally administered conjugated equine estrogens in postmenopausal women.
To determine whether vaginal administration of conjugated equine estrogens (VCE) could provide physiological replacement while avoiding effects on hepatic function, as occurs with oral administration, a study was conducted in which 20 postmenopausal women were evaluated before and after the vaginal administration of CE. The dosages studied were 0.3, 0.625, 1.25, and 2.5 mg/day for 4 weeks. Twenty premenopausal women were also studied, and their values were presumed to reflect normal physiological function. The findings in the postmenopausal women were compared with previously reported results obtained in a similar group of subjects given oral CE (OCE). Vaginal cytology returned to premenopausal values with 0.3 mg VCE. This response was similar to that exerted with 1.25 mg OCE. Stepwise increases in circulating estrone and estradiol occurred with increasing dosages. The 2.5-mg dosage of VCE raised estrone levels to values similar to those in premenopausal women in the late follicular phase, and estradiol concentrations were similar to early follicular phase concentrations. Limited or no responses of the systemic markers of estrogen action occurred with all doses of VCE. Small decreases in LH and FSH levels occurred, but no dosage significantly reduced the level of either gonadotropin. Although the urinary calcium to creatinine ratio was significantly reduced by the two largest dosages of VCE, the effect of the 2.5-mg dosage was less than that observed with 0.625 mg OCE, the lowest dosage that protects against osteoporosis. Hepatic protein synthesis was significantly increased only by the higher dosages tested. No dosage had a significant effect on circulating levels of triglycerides or total or fractionated cholesterol levels. These data suggest that the vaginal administration of CE exerts mainly a local effect, with limited or no measurable changes in systemic markers of the action of estrogen.
Administration, Oral↗
Protein-bound corticosteroid in human serum is selectively transported into rat brain and liver in vivo.
It is generally regarded that only free corticosteroid is available for entry into tissues in vivo, although some studies have suggested that albumin-bound corticosteroid is available for liver uptake. However, recent studies suggest that owing to favorable kinetic relationships among tissue capillary transit times and hormone dissociation rates from plasma proteins, free plus albumin-bound hormone may be available to peripheral tissues. Moreover, globulin-bound hormone may enter the liver under normal conditions and be available to peripheral tissues under pathological circumstances. The present studies measure the free and noncorticosteroid-binding globulin (non-CBG)-bound corticosteroid fractions in vitro and compare these measurements to the fraction of corticosteroid in human sera that is available for entry into rat brain and rat liver in vivo. Corticosterone was used as the model corticosteroid, since this compound binds to CBG with the same affinity as does cortisol, and the brain extraction of corticosterone is more readily measured in vivo than is the brain extraction of cortisol. Serum was obtained from 51 human subjects and included samples from newborns, pregnant mothers, normal subjects, and patients with either cirrhosis or renal failure. Serum levels of CBG varied more than 6-fold, and both the free and the non-CBG-bound fractions were generally inversely related to the CBG concentration. The fraction of corticosterone available for entry into the brain was much greater than the free fraction, but was not significantly different from the non-CBG-bound moiety. Moreover, the rate of corticosterone dissociation from CBG (t 1/2 = 27 +/- 1 sec at 22 C) was not increased in any of the serum samples studied. The fraction of corticosterone available for uptake by the liver was up to 3-fold greater than that of the non-CBG fraction and had no relationship with the serum concentration of CBG. These studies indicate that albumin-bound, but not globulin-bound, corticosteroid is available for entry into a peripheral tissue such as the brain. However, globulin-bound corticosteroid is readily transported into the liver. It is suggested that the routine measurements of the non-CBG-bound corticosteroid provide a more accurate index of the corticosteroid available to peripheral tissues in vivo than does the measurement of free corticosteroid.
Animals↗
Insulin resistance in nonobese patients with polycystic ovarian disease.
To determine whether insulin resistance occurs in polycystic ovarian disease (PCO) in the absence of obesity and acanthosis nigricans, circulating levels of insulin in response to oral glucose administration were measured in 10 nonobese PCO patients without acanthosis nigricans and in 10 normal women matched for weight and height. Mean serum testosterone (T), androstenedione (A), dehydroepiandrosterone (D), D sulfate, and LH levels were significantly elevated in the PCO patients compared to those in control subjects. In PCO patients, the mean +/- SE basal insulin level (18.7 +/- 2.9 microU/ml) and the sum of the insulin levels in response to glucose (674 +/- 119 microU/ml) were significantly greater than those in the control group (11.0 +/- 0.8 microU/ml and 248 +/- 29 microU/ml, respectively). In all subjects, serum levels of T and A, but not D and D sulfate, were significantly correlated to basal insulin levels and insulin sums. Serum cortisol, GH, and PRL levels were similar in both groups. These results indicate that in PCO, a significant degree of insulin resistance exists, which clearly is not related to obesity. The positive correlation of serum T and A levels to circulating insulin levels in this study suggests that the insulin resistance in PCO may be, in part, a consequence of hyperandrogenism.
Androstenedione↗
Estrogen replacement therapy: indications and complications.
Estrogen replacement therapy is one of the most controversial issues in the field of reproductive medicine. Indications for its use include hot flashes, vaginal atrophy, and risk of osteoporosis. Risk of heart disease may also be an indication but this use has not been firmly established. The role of estrogen replacement therapy in aging changes of skin needs clarification. Complications of therapy include endometrial cancer, breast cancer, hypertension, hyperlipidemia, and gallbladder disease. The last three complications presumably result from hepatic actions of estrogen replacement therapy.
Animals↗
Endogenous cortisol and sex steroids in patients with osteoporotic spinal fractures.
Vertebral fractures due to osteoporosis commonly occur in postmenopausal women. Levels of cortisol and sex steroids in the circulation vary among older women. It has been suggested that this variation may contribute to the occurrence of osteoporotic fractures in some subjects but not others. To examine this, 30 patients with osteoporotic spinal fractures were compared to an equal number of controls matched to the patients for age and years since menopause. All subjects had intact ovaries and had not taken estrogen replacement therapy for more than 3 months during their entire lifetime. Spinal bone mineral density determined by dual photon absorptiometry was significantly lower (P less than .01) in the fraction group (0.75 +/- 0.03 g/cm2) than in the controls (1.0 +/- 0.03 g/cm2). No significant differences in body habitus or cortisol and sex steroid levels (both total and free) were found, with the exception of total estradiol levels, which were 16% higher in the fracture patients. This difference was presumably coincidental as there was no difference of free estradiol levels between groups. It is concluded that factors other than the differences of endogenous cortisol and sex steroid levels present in these postmenopausal women were responsible for the reduced bone mineral density of the spine observed in the fracture patients.
Androgens↗
Hormonal effects of danazol and medical oophorectomy in endometriosis.
The hormonal effects of danazol and of a long-acting gonadotropin-releasing hormone analogue (GnRH-a) were studied in women with endometriosis and those with oophorectomy. During danazol treatment, total serum concentrations of estrone and estradiol, and free, dialyzable estradiol were reduced to the low follicular phase range for premenopausal women. Corresponding estrogen levels were suppressed to a significantly greater degree (P less than .02) at the end of GnRH-a administration, to concentrations which were twofold to fourfold lower than with danazol therapy and similar to values in the oophorectomized women. Sex hormone binding globulin was markedly suppressed (P less than .001) throughout danazol treatment, resulting in a threefold elevation (P less than .01) of free testosterone. These data suggest that danazol may affect endometriosis by mechanisms other than by inducing a pseudomenopause. The increased tissue availability of testosterone may be responsible for acne and hirsutism observed in some women during danazol treatment and may inhibit proliferation of the ectopic endometrium. Medical oophorectomy using GnRH-a may have improved effects on endometriosis without the androgenic side effects of danazol.
Castration↗
Circadian pattern of prolactin secretion in postmenopausal women receiving estrogen with or without progestin.
The circadian rhythm of prolactin secretion was assessed in postmenopausal women before and after daily administration of ethinyl estradiol for 4 weeks given in the morning (AM) or evening (PM) or in combination with a synthetic progestin, 17-medroxyprogesterone acetate. In response to AM ethinyl estradiol, mean circulating levels of serum prolactin during sleep and awake phases of the day rose 2.5-fold compared to untreated control values. The sleep/wake ratios for serum prolactin were comparable prior to and after AM administration of ethinyl estradiol. Altered time of administration, PM ethinyl estradiol or concomitant ethinyl estradiol and progestin treatment produced similar increases in mean prolactin levels, which were not different from the level observed during AM administration of ethinyl estradiol. These findings indicate that estrogen replacement therapy, in a dosage recommended for treatment of the menopause, stimulated a sustained rise in serum prolactin over 24 hours. This enhanced release of prolactin was not influenced by the time of administration of estrogen or concomitant administration of 17-medroxyprogesterone acetate.
Circadian Rhythm↗
Silastic implants of progesterone produce high circulating levels of both progesterone and 20 alpha-hydroxyprogesterone in ovariectomized, adrenalectomized rats.
Previous studies indicated that circulating 20 alpha-hydroxyprogesterone (20 alpha-OH-P) in cyclic female rats derived from enzymatic conversion of progesterone in corpus luteum tissue (Hashimoto and Wiest, 1969). A possibility of extraovarian conversion of progesterone to 20 alpha-OH-P also was revealed by our recent finding that placement of Silastic implants of progesterone produced not only high plasma progesterone but also 20 alpha-OH-P in ovariectomized (OVX), previously pseudo-pregnant, rats (Gilman et al., 1981). This study was performed to measure the amounts of serum 20 alpha-OH-P and progesterone in intact or adrenalectomized (ADX), cyclic female rats and in OVX, ADX or OVX-ADX animals with or without progesterone implants. Twenty-four-hour patterns of serum progestins revealed that OVX rats exhibited low progesterone secretion (3-6 ng/ml) and undetectable levels of 20 alpha-OH-P in the absence of ovaries. In intact, cyclic females, circulating concentrations of 20 alpha-OH-P were 4- to 6-fold greater than those or progesterone. ADX resulted in a partial reduction of progesterone but not 20 alpha-OH-P in the circulation. Placement of 4 cm Silastic implants of progesterone produced high serum concentrations of both progesterone (29 +/- 4 ng/ml, mean +/- SEM) and 20 alpha-OH-P (27 +/- 1 ng/ml) in OVX and OVX-ADX rats. These findings demonstrate that placement of progesterone implants into female rats produces high circulating concentrations of both progesterone and 20 alpha-OH-P, and indicate that an extraovarian and extra-adrenal system(s) for progestin conversion is functioning under persistently high circulating progesterone conditions. By this system, large amounts of circulating progesterone are transformed into a less potent progestational compound, 20 alpha-OH-P.
Adrenalectomy↗
Total and free estrogens and androgens in postmenopausal women with hip fractures.
Hip fracture constitutes the most serious complication of postmenopausal osteoporosis. To examine the possible role of circulating estrogen or androgen levels in the development of this type of fracture, 25 patients with hip fractures after minimal trauma were compared to an equal number of controls, matched for age and years since menopause. All were from a retirement community, had intact ovaries, and had not taken estrogen replacement for longer than 3 months during their entire lifetime. Hip fracture patients were found to have a significantly lower (P = 0.031) mean (+/-SE) percent ideal weight (89.4 +/- 2.9%) than controls (100.0 +/- 2.5%). Sex hormone-binding globulin levels were significantly higher (P = 0.004) in patients (6.7 +/- 0.4 X 10-8 M) than in controls (4.9 +/- 0.3 X 10-8 M), resulting in lower concentrations of biologically available estradiol and testosterone. In a subgroup of 12 patients and controls matched for percent ideal weight, differences in sex hormone binding globulin and free testosterone and estradiol levels were no longer statistically significant; however, the difference in the percentage of free testosterone persisted. These data suggest that endogenous sex steroids in their unbound form may play a role in the pathogenesis of postmenopausal hip fractures. The differences in free hormone levels appeared to be influenced by the differences in mean body size of the 2 groups. This factor is known to have an important negative effect on the concentration of sex hormone-binding globulin.
Aged↗
Enhanced disparity of gonadotropin secretion by estrone in women with polycystic ovarian disease.
The disassociation between serum LH and FSH levels in polycystic ovarian disease (PCO) has been attributed to chronic acyclic estrogen production characterized by a predominance of circulating estrone (E1). This study was designed to determine whether the administration of estrone benzoate (E1B) modulates gonadotropin release in PCO. In five normal women studied during the early follicular phase of a control and subsequent treatment cycle, daily LH and FSH levels were unaltered by E1B administered from days 2 to 6. Gonadotropin responses to LRF given on day 7 were similar during control and treatment cycles. In seven patients with PCO, the mean LH concentration (25.7 +/- 0.7 mIU/ml) and the daily pattern of release were unchanged by E1B administered for 14 days. In contrast, a progressive decline in FSH occurred in each subject. Mean FSH levels decreased significantly from a pretreatment value of 11.3 +/- 0.2 to 9.3 +/- 0.9 mIU/ml by day 2 (P less than 0.05) and 7.2 +/- 1.2 mIU/ml by day 14 (P less than 0.005) of E1B administration. The LH response to LRF in PCO was significantly greater than that observed in the normal subjects, whereas responses before, during, and after E1B administration were similar. The FSH responses to LRF in PCO subjects were comparable to those of the normal subjects. These data indicate that the administration of E1B to PCO subjects reduces FSH levels without altering LH release, thereby enhancing the disparity of gonadotropin secretion encountered in this syndrome. This finding is consistent with the hypothesis that impairment of FSH release by chronic acyclic estrogen production derived from nonglandular aromatization of circulating androgen could in large part be responsible for anovulation in PCO.
Estradiol↗
"Medical oophorectomy" using a long-acting GNRH agonist--a possible new approach to the treatment of endometriosis.
Five women with endometriosis were given a daily dose of a potent long-acting GnRH agonist, D-Trp6-Pro9-Net-LHRH (GnRH-A) for 28 days in an attempt to suppress ovarian estrogen secretion. The mean level of estradiol (E2) during sampling over 24 hours decreased (P less than 0.01) from 62 +/- 11 to 10 +/- 1 pg/ml at the end of treatment. Mean concentrations of androstenedione, testosterone, estrone and E2 on day 28 of therapy were similar to those measured in oophorectomized women. The level of FSH was decreased (P less than 0.001) during GnRH-a, whereas that of LH was significantly (P less than 0.001) increased, suggesting differing intracellular control mechanisms for release of the two gonadotropins. Desensitization of the pituitary was demonstrated at the end of treatment by a complete lack of acute response of FSH or LH to the daily dose of GnRH-a. "Medical oophorectomy" provides a new approach to the treatment of endometriosis.
Endometriosis↗
Effects of human cirrhotic serum on estradiol and testosterone transport into rat brain.
It is known that sex hormone-binding globulin (SHBG), which binds both testosterone and estradiol in human serum, is markedly elevated in cirrhosis. In addition, it is known that the net metabolic clearance of testosterone is decreased in cirrhosis, while no change in the metabolic clearance of estradiol is observed. Since net clearance estimates are not direct measures of plasma protein binding effects, the present studies were designed to examine the effects of cirrhotic human serum on the unidirectional clearance of sex steroids using an in vivo rat brain paradigm previously described. Cirrhotic serum was characterized by the following changes from control serum: 2.6-fold increase in SHBG, 40% decrease in albumin, and 30% and 22% decreases in the dialyzable fractions of testosterone and estradiol, respectively. In addition, the non-SHBG-bound fraction of estradiol was decreased 41% in cirrhosis, but no significant change in the brain extraction of estradiol was observed using cirrhotic serum. In contrast, the unidirectional testosterone clearance was decreased 33% by cirrhotic serum. These studies indicate that changes in the net metabolic clearance of sex steroids closely parallel the changes in unidirectional clearance caused by alterations in plasma proteins. The absence of a decrease in estradiol clearance in cirrhosis in association with the substantial decrease in the non-SHBG-bound estradiol fraction is an unexpected finding, since previous studies have shown that a close parallel exists between these two parameters. A possible explanation is that estradiol bound to the SHBG in human cirrhotic serum is partially available for transport into peripheral tissues such as the brain.
Adult↗
Circulating levels of plasma adrenocorticotropin in polycystic ovary disease.
Excessive adrenal androgen production contributes to hyperandrogenism in polycystic ovarian disease (PCO). This study was performed to determine the concentration of basal plasma ACTH in PCO patients and normal women and correlate its level with that of circulating adrenal androgen. In PCO patients, significant increases in serum testosterone, androstenedione, and dehydroepiandrosterone sulfate were noted compared to levels in normal women. The mean circulating plasma ACTH in PCO patients (22 +/- 2 pg/ml) was not different from that in normal controls (20 +/- 2 pg/ml). The mean ratio of dehydroepiandrosterone sulfate to ACTH in individual PCO patients was significantly greater than that in normal subjects, whereas the cortisol to ACTH ratio was similar in both groups. These results suggest that increased adrenal androgen production in PCO patients is not due to abnormal ACTH secretion but arises from either altered adrenal responsiveness to ACTH or abnormal adrenal stimulation by a factor(s) other than ACTH.
Adrenocorticotropic Hormone↗
Long term effects of nightly dexamethasone administration in patients with polycystic ovarian disease.
The long term effects of nightly dexamethasone administration on basal levels and diurnal fluctuations of circulating gonadotropins, androgens, and cortisol were studied by frequent sampling in four women with polycystic ovarian disease and a similar number of normal women. Basal LH, testosterone, and androstenedione levels were elevated in the patients with polycystic ovarian disease. There were significant diurnal variations of all steroids measured in both groups, with the exception of androstenedione and androstenediol in the polycystic ovarian disease and control subjects, respectively. Nightly dexamethasone administration for 1 month resulted in marked suppression of dehydroepiandrosterone, androstenediol, and cortisol. For testosterone the mean percent decreases of the 24-h transverse means were 15% and 46% for the polycystic ovarian disease and normal subjects, respectively. For androstenedione the mean percent decreases were only 7% and 20%, respectively. The diurnal variation of all steroids disappeared with dexamethasone. These results support the concept that in patients with polycystic ovarian disease the majority of delta 5-androgens is adrenal while the preponderance of elevated testosterone and androstenedione is ovarian in origin. These results do not support the use of long term dexamethasone as an effective agent in suppressing the elevated levels of testosterone and androstenedione in patients with this disease.
Adult↗