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Hypothyroidism in the human female is often associated with ovarian follicular cysts and hyperandrogenism, two cardinal signs of polycystic ovary syndrome. To explore the intraovarian changes that lead to follicular cyst formation in hypothyroidism, we have created a prepubertal hypothyroid rat model. These hypothyroid rats are hyperandrogenic and develop transient ovarian follicular cysts. Hypothyroidism in newborn rats was induced by providing the lactating dams with 0.04% propylthiouracil (PTU)-containing water. Subsequently, female rats were weaned and kept on PTU-containing water. On Day 25 of age, the rats were primed with 15 international units of pregnant mare's serum gonadotropin (PMSG) in 100 microl of phosphate buffered saline. Two days later, to initiate pseudopregnancy, they were injected with five international units of human chorionic gonadotropin (hCG). The animals were sacrificed at appropriate times, and blood and ovaries were collected for analyses. Control experiments were done with euthyroid rats. Two days after PMSG injection, well-developed antral follicles were observed in both the hypothyroid and euthyroid rats. Two days after hCG injection, while the euthyroid rat ovaries, as expected, contained numerous corpora lutea (CL), the hypothyroid rat ovaries still retained antral follicles. Some of these follicles with degenerating oocytes showed signs of luteinization. By 3-4 days post-hCG injection, the hypothyroid rat ovaries developed cystic follicles. By Day 6, however, the hypothyroid rat ovaries were indistinguishable from those of the euthyroid rats. Although serum testosterone concentrations were significantly elevated in the hypothyroid rats on Days 1-3, progesterone concentrations were not significantly different from the euthyroid animals. However, by Days 8-14, the hypothyroid rats had significantly higher serum progesterone concentrations. This model will be useful for investigating the intraovarian biochemical changes that lead to follicular cyst development in response to acute gonadotropin treatment.

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This study extends previous observations of the conditions under which enhancement of lymphocyte activity occurs following cold swim stress and presents a possible explanation for the enhancement observed. Eight- to twelve-week old male Sprague-Dawley rats swam for 10 minutes daily for one, three, or five days in cold water at 15 degrees C and were killed 0, 30, or 240 minutes following the last swim. Apparatus control animals were placed into an empty swim tank for 10 minutes and then returned to their home cages. Home cage control animals were not manipulated experimentally at all. Splenocyte but not thymocyte responses to concanavalim A were significantly enhanced after one, three, and five days of stress. This enhancement was seen after 0, 30, and 240 minutes of recovery and also in the apparatus controls! The number of splenocytes did not change significantly, but thymocyte number declined following the swims. The blood displayed no changes in leukocyte percents. Serum corticosterone levels were significantly higher and serum testosterone levels were significantly lower after one, three, and five days of stress. The drop in testosterone levels may have released the lymphocytes from inhibition by this hormone, resulting in increased responsiveness. There were significant elevations in levels of blood glucose and protein following one, three, and five days of stress sessions, correlated with the increases in serum corticosterone.

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It is not known why hypothyroidism predisposes the ovary to develop cystic follicles in hCG-treated rats. This study examined the effect of TSH on steroidogenesis in cultured granulosa cells. Granulosa cells were isolated from the ovaries of hCG-treated Long-Evans rats. Cells were cultured in medium with either 0 or 100NM: testosterone or 25(OH)cholesterol and treated with 0, 2.5, 10 or 20 ng/ml of TSH. TSH reduced 3ß-HSDI activity in these cells to 12% of control. Progesterone secretion decreased by 72% and estradiol secretion was non-detectable during the second day of treatment with 20 ng/ml of TSH. We conclude that TSH is capable of regulating the secretion of progesterone and estradiol by cultured granulosa cells.

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Hypothyroid rats develop cystic follicles after daily administration of human chorionic gonadotropin (hCG). This study was undertaken to compare progesterone, testosterone, and estradiol secretion by antral follicles (0.9-1.0 mm) and cysts (small; 1.2-2.0 mm; large: > 2.0 mm) from hypothyroid, hCG-treated rats with that of antral follicles from euthyroid, saline-treated animals. After 3, 5, or 10 days of hCG injections, follicles and cysts were dissected from the ovaries, diameter determined, and incubated in minimum essential medium (MEM) for 2 hr at 37 degrees C. Media were assayed for progesterone, testosterone, and estradiol by RIA. Progesterone secretion by antral follicles removed after 3, 5, or 10 days was similar but small cysts secreted significantly more of this steroid than did antral follicles. Large cysts secreted significantly more progesterone than all other follicles and cysts. After 10 days of treatment with hCG, antral follicles from hypothyroid, hCG-treated rats secreted two to three times more testosterone than similar follicles from euthyroid, saline-treated animals. Changes in estradiol secretion were not apparent until after 10 days of hCG treatment. Both small and large cysts from those animals secreted significantly more estradiol than all other follicle and cyst groups. These results suggest that steroid secretion by follicles and cysts could be contributing to elevated serum levels of progesterone and testosterone during the first 10 days of cyst induction. However, cysts may be contributing estradiol only during the later stages of cyst induction.

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All of the steroidal anti-inflammatory drugs currently available are glucocorticoids. They exhibit both glycogenic and anti-inflammatory activities. These two activities are usually considered inseparable. This glycogenic activity is responsible for most of the adverse side effects that severely limit clinical use of currently available steroidal anti-inflammatory drugs. The purpose of this study was to determine if a steroid, 16-epiestriol, could exhibit significant anti-inflammatory activity without glycogenic activity. The anti-inflammatory activity of 16-epiestriol was determined using a modified Winter's carrageenin rat paw edema model. The glycogenic activity of 16-epiestriol was determined by a modification of Venning's methods on liver and plasma glucose concentrations. In each study, 16-epiestriol-treated animals were compared to untreated control and hydrocortisone-treated animals. In the anti-inflammatory study, 16-epiestriol was more than twice as effective as hydrocortisone, on an equimolar basis, in preventing edema. 16-Epiestriol exhibited no effect on the liver or plasma glucose concentration in the glycogenic study. 16-Epiestriol exhibited potent anti-inflammatory activity without glycogenic activity. 16-Epiestriol does not conform to classical steroidal structure-activity relationship theory.

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Serum testosterone concentrations are reduced in men with rheumatoid arthritis and in rats with adjuvant-induced arthritis, a common model for rheumatoid arthritis. To understand the mechanism responsible for this reduction, testosterone production by testicular cells and Percoll-purified Leydig cells from nonarthritic and arthritic rats was studied. Leydig cells in crude interstitial cell preparations from arthritic rats secreted significantly less testosterone in response to human chorionic gonadotropin (hCG) stimulation than cells from nonarthritic animals. In contrast, no differences in hCG and dibutyryl cyclic adenosine monophosphate-stimulated testosterone production by Percoll-enriched Leydig cells from arthritic and nonarthritic animals were observed. To determine whether a secretory product from testicular macrophages was important to this reduction, macrophages from arthritic and nonarthritic animals were cultured. The conditioned media from these cultures were added to cultures of interstitial cells from nonarthritic animals. Nonarthritic rat testicular macrophage-conditioned medium had no significant effect on testosterone production. In contrast, conditioned medium from arthritic rat testicular macrophages significantly reduced testosterone production. These results suggest that testicular macrophages secrete a factor that may be important in the regulation of testosterone production in the adjuvant-induced arthritic rat.

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The induction of polycystic ovaries in hypothyroid rats by human chorionic gonadotropin (hCG) has been studied for many years. A complete understanding of this phenomenon requires information regarding the circulating levels of the hormones of the hypophyseal-gonadal axis. In this study, serum prolactin (PRL), luteinizing hormone (LH), estradiol, testosterone, and progesterone were measured by radioimmunoassay at intervals during the 40-day period in which large ovarian cysts were induced in hypothyroid rats by daily injections of hCG. After 20 injections, ovaries increased in weight 10-fold, and well-developed ovarian cysts were present, accompanied by lutein tissue; cyst development continued for the subsequent 20 days of hCG. Both PRL and LH rose during the first 5 days of treatment and were maintained at high levels from day 20 on. The pattern of change of gonadal steroids showed greater increases with hCG in hypothyroid than in euthyroid rats. Levels of estradiol in hypothyroid, hCG-injected rats increased in parallel to ovarian hypertrophy, whereas progesterone was high in initial stages and then declined. Testosterone increased in both euthyroid and hypothyroid animals, with no clear pattern coincident with cyst formation. The data suggest that the formation of polycystic ovaries in the hypothyroid rat is associated with high levels of PRL and LH followed by elevations of estradiol, which may serve to maintain continuous PRL, as well as LH, stimulation of the ovary.

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The hypothalamic-pituitary-testicular (H-P-T) axis was evaluated in groups of endurance-trained (TRG) and untrained (UNT) males. Each group was subjected to: 1) a 4-h resting hormonal profile [testosterone (T), free-testosterone (FT), estradiol (E2), luteinizing hormone (LH), prolactin (PRL), and cortisol (C)], 2) a dopamine antagonist (DA; 10 micrograms.kg-1 body weight) challenge to the pituitary-testes, and 3) a gonadotropin-releasing hormone (GnRH; 120 micrograms.kg-1 body weight) challenge to the pituitary-testes. Compared to UNT, the TRG resting T (4.8 +/- 0.7 vs 7.1 +/- 1.2 ng.ml-1, p = 0.05) and PRL (3.3 +/- 1.4 vs 7.0 +/- 2.3 ng.ml-1, p = 0.09) were lower while LH was elevated (15.0 +/- 1.8 vs 11.8 +/- 1.5 mIU.ml-1, p = 0.06). The DA challenge produced a greater integrated PRL response in the TRG (2962.7 +/- 265.1 ng +/- ml-1.min) than in the UNT (1735.3 +/- 282.0 ng.ml-1.min; p = 0.01). No significant changes were observed in T following the DA-induced PRL rise. The TRG had a blunted LH response (817.2 +/- 111.6 mIU.ml-1.min) following the GnRH injection as compared to the UNT (1493.7 +/- 213.4 mIU.ml-1.min; P less than 0.02). T levels were significantly (p less than 0.03) increased in both groups by the LH rise after the GnRH challenge (TRG = 9.9 +/- 5.0%; UNT = 8.6 +/- 9.9%, respectively), but no significant between group differences were observed. Results suggest endurance training produces an enhanced PRL and attenuated LH release by the pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)

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Adjuvant-induced arthritis, an autoimmune disease similar to rheumatoid arthritis, was used to investigate possible mechanisms of immune system modulation of the reproductive system. This laboratory previously reported that arthritic male rats have reduced serum testosterone and elevated serum LH concentrations. In the experiments described here, serum prolactin levels were not significantly different in arthritic animals compared with non-injected control animals. Neither reduced food consumption of arthritic rats nor the injection vehicle appear to cause a reduction of serum testosterone. Serum corticosterone was significantly elevated in the arthritic group compared with both the non-injected or the vehicle-injected control animals. Testicular cells from arthritic animals secrete significantly less testosterone in vitro compared with cells from non-injected control animals, both basally and in response to dbcAMP and hCG. In summary, the reduced serum testosterone of arthritic animals appears to be the result of a testicular dysfunction.

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Nine pregnancy test kits intended for home use were evaluated for optimal accuracy, sensitivity, ease of operation, and definitude of results. Tests of the kits on samples of urine from healthy male volunteers previously spiked with known concentrations of human chorionic gonadotropin showed wide variations among the kits in all characteristics examined. Specific values are given for the kits tested.

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This study compares the resting reproductive hormonal profiles of untrained (N = 11) and endurance-trained (N = 11) males. Testosterone, free testosterone, estradiol, luteinizing hormone (LH), prolactin, and cortisol were measured by radioimmunoassay in resting blood samples (8 h fast) collected every 60 min for 4 h. The endurance-trained group had been active for (mean +/- SE) 12.4 +/- 6.7 yr, 6.6 +/- 0.2 d.wk-1, 68.5 +/- 4.4 min.d-1, while the untrained group was sedentary. Neither group had histories of hypothalamic-pituitary-testicular disorders. The overall 4 h mean testosterone and free testosterone levels were significantly (P less than 0.05) lower in the trained group (4.99 +/- 0.46 vs 7.25 +/- 0.67 ng.ml-1, and 17.2 +/- 1.4 vs 23.6 +/- 0.6 pg.ml-1, for the trained and untrained groups, respectively). The LH of the endurance-trained group was higher (15.3 +/- 1.9 vs 11.7 +/- 1.2 mIU.ml-1, P = 0.06); however, LH pulse frequency and amplitude did not differ between groups. An enhanced estradiol feedback to the hypothalamus-pituitary could not account for the elevated LH, as estradiol levels were similar in the groups. Prolactin and cortisol levels were normal and did not differ between groups. The results suggested normal hypothalamic-pituitary function existed in the trained subjects, and prolactin and cortisol were not causative factors in the lowered resting testosterone and free testosterone levels. The findings indicate that chronic endurance training lowers testosterone and free testosterone in males possibly by impairing testicular function.

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There is evidence that melatonin may exert its antigonadal effect by acting in the gonad to inhibit steroidogenesis. To explore this possibility a hormonally sensitive in vitro system of dispersed Peromyscus leucopus testis was used to assess the effects of melatonin on human chorionic gonadotropin (hCG)- and dibutyryl-cAMP (dbcAMP)-stimulated secretion of testosterone (T). At near-maximally stimulating doses of hCG and dbcAMP, melatonin in concentrations of 2 x 10(-12) M to 2 x 10(-7) M did not affect the rate of secretion of T in cells from active or regressed testes. These results do not support the idea that melatonin helps to regulate seasonal reproduction by acting in the testes to inhibit steroidogenesis.

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Male Lewis rats were made arthritic by injecting 1 mg Mycobacterium butyricum suspended in Freund's incomplete adjuvant into their right hind footpad. Arthritic and non-arthritic animals were sacrificed on days 18, 21, 24 or 27 after the injection of the adjuvant. Body weight, left and right hind paw volume, thymus weight, and serum luteinizing hormone (LH) and testosterone concentrations were determined on each day. Adjuvant injection resulted in a significant enlargement in the left and right hind paws on days 18 through 27. In contrast, body and thymus weights were reduced significantly in the arthritic rats compared to the non-arthritic animals. Serum concentrations of testosterone were also reduced significantly in arthritic rats on days 18, 21 and 24 after the injection of the adjuvant. However, by day 27 serum testosterone concentrations recovered to near control values. Serum concentrations of LH in the arthritic animals were elevated on days 18 through 27. These results demonstrate that serum testosterone concentrations were reduced in rats with adjuvant-induced arthritis. The reduction in serum testosterone is probably not the result of an impaired hypothalamic-pituitary axis.

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The purpose of this investigation was to determine whether exercise at different times of the menstrual cycle alters protein catabolism. Nine women exercised for 60 min at 70% VO2max when serum estradiol (E) and progesterone (P) were low (menses) and when both were high [mid-luteal (ML)]. Diet was reproduced on both occasions. Serum urea nitrogen (N), E, and P were analyzed at rest, after 15, 30, 45, and 60 min of exercise, and 15 min into recovery. Sweat urea N excretion was also determined. Urinary area N excretion was measured the day before, the day of, and 2 d following exercise. E and P were significantly greater in the ML phase, and this difference was maintained throughout exercise (P less than 0.05). No change was seen in serum urea N across exercise or between phases. Both exercise day urinary urea N excretion and total urea N excretion in sweat and urine, when added across all experimental days, were significantly greater in the ML phase compared to menses (8.5 +/- 0.96 vs 5.5 +/- 0.81 g and 24.8 +/- 2.38 vs 19.3 +/- 1.38 g, respectively, P less than 0.05). The data suggest that the greater protein use in the ML phase was due to the combined effects of exercise, a changing hormonal milieu and other unknown causes.

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This study was undertaken to examine ovarian steroid production during the early stages of hCG-induced ovarian cyst formation in the hypothyroid rat. Rats were placed into two groups with one group made hypothyroid by adding thiouracil to their diet. After 10 days, each group was divided into two subgroups with one subgroup receiving daily injections of hCG for 2 days and the other subgroup receiving saline. On the morning of Day 13, ovaries were removed and incubated for 2 hr. No significant difference in progesterone secretion was observed. However, ovaries from hypothyroid, hCG-treated rats secreted significantly more testosterone and estradiol than ovaries from vehicle-treated, hypothyroid rats and euthyroid, hCG-treated rats. In a second experiment, ovaries from euthyroid and hypothyroid rats treated with hCG were incubated in medium supplemented with 100 nM androstenedione and 0 or 100 ng FSH/ml. FSH failed to affect progesterone, testosterone, and estradiol secretions by ovaries from euthyroid, hCG-treated rats. In contrast, FSH significantly enhanced testosterone and estradiol secretion by ovaries from hypothyroid, hCG-treated rats. These results support the hypothesis that increased levels of testosterone and estradiol secretion have a central role in the induction of polycystic ovaries by hCG in the hypothyroid rat.

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The daily administration of human chorionic gonadotropin (hCG) to rats with thiouracil-induced hypothyroidism results in the development of cystic ovaries. This study was undertaken to delineate hormonal changes during the first 48 h of hCG treatment. Groups of euthyroid and hypothyroid rats were injected daily with hCG or saline for up to two days and killed at 0, 12, 24, or 48 h after the initial hCG injection. Sera were analyzed for progesterone (P), testosterone (T), 17 beta-estradiol (E2), and prolactin (Prl) by specific radioimmunoassay (RIA). Serum levels of these hormones were not significantly different in the euthyroid and hypothyroid rats. However, P was significantly elevated at 12, 24, and 48 h in the hypothyroid/hCG rats. T and Prl were significantly elevated at 12 and 48 h in the hypothyroid/hCG rats. T levels were also elevated at 12 and 48 h in the euthyroid rats receiving hCG. In contrast, hCG had no effect on P and Prl levels in the euthyroid rats. E2 levels were undetectable in the euthyroid and hypothyroid rats. The administration of hCG increased E2 in both the euthyroid and hypothyroid rats at 48 h with significantly more E2 detected in the hypothyroid rats. These results show that ovarian steroids and Prl levels increase during the early stages of cyst induction and suggest they may be important in triggering ovarian cyst formation.

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Primates are believed to have a low level of ovarian steroidogenic activity during prepubertal development. In order to study the rate limiting factors associated with the low level of steroidogenesis, ovaries from prepubertal rhesus monkeys were quartered and incubated for 48 h at 37 C in minimum essential medium. These ovaries secreted 687 +/- 347 pg estradiol/mg ovary and 299 +/- 35 pg progesterone/mg ovary during 48 h of incubation. The addition of 100 ng luteinizing hormone (LH) or 1 mM dibutyryl (Bu)2 cAMP failed to increase significantly estradiol or progesterone secretion. Furthermore, the addition of either progesterone or androstenedione failed to augment estradiol secretion. The presence of either LH or (Bu)2 cAMP with the steroidal substrates also failed to augment estradiol secretion. In contrast, the addition of (Bu)2 cAMP with lipoprotein-derived cholesterol significantly stimulated a two-fold increase in progesterone secretion. The presence of LH in the lipoprotein-supplemented medium failed to augment progesterone secretion. These results suggest that prepubertal monkey ovaries lack the ability to respond to LH, probably due to a lack of gonadotropin receptors or failure of the receptor to stimulate cAMP synthesis. Furthermore, the failure of progesterone and androstenedione to augment estradiol secretion suggests that some cellular components needed to induce aromatase activity are not functional in the prepubertal primate ovary.

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Release of progesterone from enzymatically dispersed luteal cells of superovulated rats was studied using a multi-channeled perifusion system. Cells were perifused with protein-free medium for up to 5 h. Basal release of progesterone showed a steady decline during the first h of perifusion to a stable baseline where it remained throughout the experiment. A 30-min exposure of the luteal cells to increasing amounts of luteinizing hormone (LH) stimulated a dose-dependent increase in progesterone release. Similar results were observed when luteal cells were exposed to 0.2 or 1.0 mM dibutyryl (Bu)2 cAMP for 30 min. Exposure of the cells to 0, 1, 10, and 100 ng LH/ml protein-free medium for 230 min showed increased release of progesterone, although the dispersed cells perifused with 100 ng LH/ml protein-free medium were unable to maintain the maximal levels of progesterone release. The effect of bovine serum albumin (BSA) in the perifusion medium on the basal and LH-stimulated progesterone release was examined. Low concentrations of BSA (0.05%) had no effect, but 0.5% and 2.0% BSA significantly increased the basal release of progesterone. However, the addition of 0.05% BSA to the medium resulted in an increased progesterone release in response to 10 ng LH/ml medium. These results suggest that the in vitro perifusion system maintains physiologically viable cells which are responsive to either LH or (Bu)2 cAMP for at least 5 h. The effect of protein in the perifusion medium or progesterone release was demonstrated by the addition of BSA.

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Immature female rats, superovulated and treated daily for 3 days with 4-aminopyrazolo-(3,4-d)pyrimidine (APP), showed a marked reduction in plasma cholesterol levels, which is reflected by reduced levels of very low density, low density (LDL), and high density (HDL) lipoproteins. Luteal cells from non-APP-treated rats released 2444 +/- 212 ng progesterone/mg protein in 4 h, which slowly increased to 2806 +/- 327 after 20 h. Luteal cells from APP-treated animals showed a similar pattern at about half the level of progesterone production. In the presence of 100 ng LH/ml, progesterone levels were stimulated 2-fold in both APP-treated and nontreated controls. The addition of either human HDL or LDL to any of the preparations markedly increased the progesterone level. These results support the hypothesis that APP treatment reduces the ability of dispersed luteal cells to secret progesterone. This effect is partially overcome by the addition of either HDL or LDL to the incubation media in vitro, suggesting that rat luteal tissue can use either human HDL or LDL as a source of cholesterol. However, about 5 times as much human LDL-derived cholesterol was required to stimulate equivalent increases in progesterone compared to human HDL cholesterol.

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