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PubMed1996

Ovary mediates the effects of RU486 given during proestrus on the diestrous secretion of luteinizing hormone in the rat.

The aim of these experiments was to study the action of proestrous afternoon follicular progesterone secretion on the preovulatory secretion of gonadotropins in the rat. Four-day-cycling rats were given 4 mg of the antiprogestagen RU486 in the morning of proestrus (Day 1), and its effects on the pituitary function during diestrus were compared with those of RU486 given in the morning of estrus (Day 2). The pituitary function was assessed by measuring basal secretion of LH and FSH as well as the pituitary response to either estradiol benzoate (EB) (3 mug/100 g BW at 1300 h on Day 3) or LHRH (100 ng/rat at 1200 h on Day 4). In all experiments, trunk blood was taken at 1300 h on Day 4 to measure serum gonadotropin concentrations. In rats receiving an injection of RU486 on estrus, the absence of only the diestrous progesterone actions increased basal serum concentrations of LH and decreased those of FSH, and as in vehicle-treated controls, EB inhibited and LHRH stimulated LH secretion. In contrast, the absence of both proestrous afternoon and diestrous progesterone actions (as characterized rats treated with RU486 on proestrus) antagonized the inhibitory effect of EB and sensitized the pituitary to LHRH. These effects of RU486 on proestrus are ovary-dependent and eliminated by ovariectomy on metestrus. The increased ovarian secretion of testosterone and estradiol-17 beta during diestrus does not mediate the effects of proestrus-administered RU486 on pituitary function: no differences were found in the serum concentrations of estradiol-17 beta in diestrus between the groups of rats treated with RU486, and administration of the antiandrogen flutamide (2 mg/rat at 0900 h on Days 2 and 3) did not reverse the effects of RU486 on proestrus. In conclusion, the results suggest that in the absence of proestrous afternoon progesterone action, the ovaries of the 4-day-cyclic rat keep the pituitary gland in a state of low sensitivity to the inhibitory effects of estradiol and high sensitivity to the stimulatory effects of LHRH. Moreover, the results suggest that the putative ovarian factors involved are factors other than progesterone, androgens, or estradiol-17 beta.

Androgen Antagonists↗
PubMed2006

Cox7a2 mediates steroidogenesis in TM3 mouse Leydig cells.

AIM: To investigate the regulatory function of Cox7a2 on steroidogenesis and the mechanism involved in TM3 mouse Leydig cells. METHODS: The cDNA of Cox7a2 was cloned from TM3 mouse Leydig cells. It was subcloned to pDsRed-Express-N1 and transfected back into TM3 mouse Leydig cells for Cox7a2 overexpression by transient gene transfection. Steroidogenesis affected by overexpressed Cox7a2 was studied by ELISA. To elicit the mechanism of this effect, expression of steroidogenic acute regulatory (StAR) protein and reactive oxygen species (ROS) were examined by Western blot and fluorometer, respectively. RESULTS: The cDNA of Cox7a2 (249 bp) was cloned from Leydig cells and confirmed by DNA sequencing. After constructed pDsRed-Express-N1-Cox7a2 was transfected back into TM3 mouse Leydig cells, Cox7a2 inhibited not only luteinizing hormone (LH)-induced secretion of testosterone but also the expression of StAR protein. At the same time, Cox7a2 increased the activity of ROS in TM3 mouse Leydig cells. CONCLUSION: Cox7a2 inhibited LH-induced StAR protein expression, and consequent testosterone production, at least in part, by increasing ROS activity in TM3 mouse Leydig cells.

Animals↗
PubMed1993

The XY female in sport: the controversy continues.

The summer and winter Olympic Games have been accompanied by much press coverage of the controversy and confusion over sex tests for sportswomen. Much of this has centred on the eligibility of subjects with androgen insensitivity to compete in women's events. The purpose of this paper is to review the process of sex differentiation and its abnormalities, highlighting those conditions in which biologically active testosterone is secreted which might confer an advantage in women's sporting events.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2000

Androgen regulation and site specificity of angiotensinogen gene expression and secretion in rat adipocytes.

Adipose tissue is an important source of angiotensinogen (ATG), and hypertension is commonly associated with android obesity. Therefore, we tested the hypothesis that androgens may control ATG gene expression and secretion in rat fat cells. In intact male rats, ATG mRNA expression (Northern blot and co-reverse transcription-polymerase chain reaction analysis) and protein secretion were significantly higher in deep intra-abdominal (perirenal and epididymal) than in subcutaneous adipocytes. After castration, ATG mRNA was reduced almost 50% in the three fat deposits, with parallel changes in ATG protein secretion. Conversely, testosterone treatment fully restored the ATG mRNA decrease after castration, whatever the anatomical origin of the adipocytes. Finally, a 24-h in vitro exposure of perirenal fat cells or differentiated preadipocytes from castrated rats to testosterone or dihydrotestosterone (10 nM free hormone concentration) increased ATG mRNA expression by 50-100%, an effect that was prevented by the anti-androgen cyproterone acetate. These data, demonstrating both in vivo and in vitro androgen induction of ATG mRNA expression in rat adipocytes, add further weight to the hypothesis of a link between adipose tissue ATG production, androgens, and android obesity-related hypertension.

Adipocytes↗
PubMed2003

Growth hormone insufficiency and its impact on ovarian function.

Growth hormone (GH) and the insulin-like growth factor-I (IGF-I) play significant roles in pubertal development, menarche, the menstrual cycle, fertility, and reproduction. Growth hormone deficiency or insufficiency causes a delay in the onset of puberty and in its normal course unless treated with synthetic GH. It seems that GH affects the ovary during puberty both indirectly through the gonadotropins and IGF-I, and directly through its effect on steroidogenesis. The GH axis is activated by small increases in circulating estrogens, which initiate large increases in GH during puberty. The reproductive function of the female is also affected by GH. GH acts on the ovary affecting gametogenesis and steroidogenesis. GH receptor mRNA and protein have been found in ovarian cells, and this suggests that the direct action of GH provides an important modulatory effect on gonadotropin-dependent and -independent functions. It also affects the maturation of the follicle and gamete, and thereby plays a facilitatory role in fertility. The majority of women with GH-deficiency, but not all, require assisted reproductive technologies to induce ovulation. Many women with polycystic ovary syndrome (PCOS) have an impaired GH response to stimulation with Levo-Dopa and GH releasing hormone (GHRH). Hyperandrogenism in PCOS may contribute to the reduced GH secretion because testosterone directly stimulates somatostatin release. Reduction of the excessive androgens facilitates the dopaminergic control of GH. In conclusion, GH-insufficient states disrupt ovarian function, causing problems in sexual maturation, the menstrual cycle, and the reproductive ability of the female.

Adolescent↗
PubMed1985

Leydig cell function in boys following treatment for testicular relapse of acute lymphoblastic leukemia.

Current practice for achieving local control of testicular relapse in males with acute lymphoblastic leukemia (ALL) includes the use of 2,400-rad testicular radiation. Although this therapy is known to cause germ cell depletion, it has been assumed that it does not alter testicular secretion of testosterone. To test this assumption, we measured gonadotropin and testosterone levels in seven boys with ALL who had been treated with radiation for clinically apparent testicular relapse. In four of seven boys, testicular relapse was bilateral with overt involvement of one testicle and microscopic involvement of the other. Three of these four boys demonstrated delayed sexual maturation, and in addition to elevated follicle-stimulating hormone (FSH) concentrations, testosterone levels were low and luteinizing hormone levels were elevated compared with controls. These data indicate that boys with overt testicular leukemia who are treated with 2,400-rad testicular radiation are at risk for Leydig cell dysfunction. However, the relative contributions of radiation, prior chemotherapy, and leukemic infiltration to this dysfunction remain to be clarified.

Adolescent↗
PubMed2004

beta-Cell function: a key pathological determinant in polycystic ovary syndrome.

We report data from 60 patients with polycystic ovary syndrome (PCOS) who had undergone assessment of insulin resistance, pancreatic beta-cell function, obesity, and androgen levels to elucidate the complex relationships among these traits. Homeostasis model assessment was used to quantify insulin resistance and beta-cell function. A reference population was derived from the National Health and Nutrition Examination Study (NHANES III, 1988-1994). Indices of insulin resistance, insulin secretion, bioavailable testosterone, and body mass index all exhibited significant pairwise correlations. Multiple regression analysis clarified the phenotypic relationships, demonstrating that insulin resistance and bioavailable testosterone were independent predictors of beta-cell function; beta-cell function and obesity were independent predictors of insulin resistance; and beta-cell function was an independent predictor of bioavailable testosterone. Of note, comparison with normal women from NHANES revealed a significantly stronger relationship between beta-cell function and insulin resistance in PCOS, raising the possibility of an intrinsic defect in beta-cell function whereby increasing insulin resistance leads to a greater insulin response in PCOS than normal. The altered relationship of beta-cell function and insulin resistance coupled with the fact that beta-cell function, not insulin resistance, was a predictor of hyperandrogenemia suggests that beta-cell dysfunction may be a key pathogenic determinant in PCOS.

Adult↗
PubMed1982

Stereological analysis of Leydig cell ultrastructure in aged humans.

Stereological analysis of Leydig cell ultrastructure in aged humans was performed by a point-count method on testicular tissues fixed by perfusion with buffered glutaraldehyde. In six aged human males (74 yr old on the average), interstitial tissue occupied 38.9% of decapsulated testis volume, and Leydig cells constituted 3.1% to total tests volume. One cubic centimeter of the testis contained about 7.7 x 10(6) Leydig cells, each of which had a volume of 4,080 micrometer3 on average. Smooth endoplasmic reticulum of Leydig cells occupied 13.4% of cell volume and had a surface area of 2,474 cm2/cm3 testis tissue or 32,000 micrometer2/cell, which was 70.7% of the total membrane area of the cell. Occupying 5.8% of the cell volume, mitochondria had an inner membrane surface area of 434 cm2/cm3 tissue or 5,600 micrometer2/cell, which was 12.4% of the total membrane area of the cell. Relating these stereological values to published data on testosterone (T) secretion rate, an average human Leydig cell would secrete about 20 pg T/day. Each cm2 of smooth endoplasmic reticulum and mitochondrial inner membranes of human Leydig cells would produce 70 ng and 400 ng T/day, respectively.

Aged↗
PubMed1988

Hyperinsulinemia and stromal luteinization of the ovaries in postmenopausal women with endometrial cancer.

Ovarian secretion of testosterone and androstenedione is increased in postmenopausal women with endometrial cancer, and insulin stimulates ovarian stromal androgen synthesis in vitro. We undertook this study to investigate whether women with endometrial cancer have increased serum immunoreactive insulin levels. Ten postmenopausal women with endometrial carcinoma and 10 postmenopausal women without cancer who matched the cancer patients in age, years since menopause, and percentage of ideal body weight were studied. The women with endometrial cancer had significantly higher fasting serum insulin levels than the normal women [mean, 187 +/- 26 (+/- SE) vs. 55 +/- 11 pmol/L; P less than 0.01]. The cancer patients had significantly higher insulin responses after glucose administration than normal women (sum of 1, 2, and 3 h postglucose values, 5545 +/- 1526 vs. 1444 +/- 156 pmol/L; P less than 0.02), even though their glucose responses were similar. Nests of luteinized cells, which were positive for testosterone by immunoperoxidase staining, were found in the ovarian stroma of 8 of the women with endometrial cancer, but in only 1 of those without cancer (P less than 0.01). Specific high affinity insulin receptors were demonstrable in the stroma of the postmenopausal ovaries. These results suggest that the frequency of stromal luteinization is increased in women with endometrial cancer and that insulin may play a role in the pathogenesis of this luteinization.

Adenocarcinoma↗
PubMed1995

Angiotensin II modulates steroidogenesis in granulosa and theca in the rabbit ovary: its possible involvement in atresia.

Accumulating evidence has shown the ovary of mammals to contain an intrinsic renin-angiotensin system that has been ascribed an autocrine-paracrine role. The present study in the female rabbit ovary investigated the putative in vitro action of angiotensin II (A II) on basal and gonadotropin-induced steroidogenesis. Ovarian follicles from immature female rabbits treated with pregnant mare's serum gonadotropin (PMSG) were dissected out and a complete separation of the theca interna from the granulosa layer was performed, to demonstrate that A II affects separately the two individual cellular components of the follicular wall. We could show that theca is a source of estradiol whose production under human chorionic gonadotropin (hCG) stimulation was reduced by A II. At the same time, A II increased the in vitro hCG-stimulated secretion of testosterone by theca. In granulosa, A II decreased hCG-stimulated aromatization of androstenedione to estradiol but did not alter the release of hCG-stimulated progesterone production. These results suggest that A II could induce locally an increase in follicular fluid androgen/estrogen ratio and possibly participate in causing atresia.

Angiotensin II↗
PubMed1976

A study of seasonally delayed puberty in the male hare, Lepus Europaeus.

The brown hare, Lepus europaeus, has a mating season which extends from January to September. Adult males exhibit pronounced seasonal changes in the reproductive tract which are associated with changes in LH secretion. Maximum plasma levels of immunoreactive LH occur between March and June and minimal levels in the autumn non-mating period from September to December; this seasonal cycle in gonadotrophin output is reflected by the appropriate changes in the secretion of testosterone from the testes and in the activity of the accessory sex glands. Juvenile animals reach puberty only during the adult mating season, and the age of puberty thus varies with the date of birth. Males born before May reach puberty and become fertile at 3 months of age, while those born from May to July grow to a mature body size during the autumn non-mating season but puberty is delayed for several months. Since some animals experiencing delayed puberty were found to have elevated plasma levels of LH and testosterone, it is concluded that puberty is not completely suppresed by the environmental effects of the autumn, but that the developmental process is prolonged, resulting in the juveniles being synchronized with the adults in their reproductive activity.

Age Factors↗
PubMed1977

Reproductive function in prepubertal lambs: ovulation, embryo development and ovarian steroidogenesis.

When 23 10-16 week-old Welsh Mountain lambs were treated with PMSG 19 ovulated, the number of eggs ovulated being directly correlated with the duration of progesterone pretreatment (0-5 +/- 0-29 (S.E.M.) after 3 days; 7-8 +/- 3-47 after 18 days). Injection of HCG at the time of the induced oestrus had no effect on ovulation. The eggs shed from immature ovaries became fertilized and developed normally when tested in the ligated rabbit oviduct for development to the morula stage and by transfer to adult ewes (1 live lamb). Luteal function in lambs with a single CL was similar to that in nonpregnant ewes; progesterone levels in entire lambs with multiple CL and in hysterectomized lambs remained elevated for at least 60 days. The capacity of ovarian follicles from PMSG-primed lambs to secrete oestrogen, testosterone and progesterone in vitro was similar to that of follicles from adult ewes. However, oestrogen production by lamb follicles immediately after explantation was higher than that of adult follicles and the administration of progesterone to lambs before PMSG treatment decreased subsequent follicular testosterone production.

Animals↗
PubMed1992

Influence of photoperiod on the seasonal pattern of secretion of luteinizing hormone and testosterone and on the antler cycle in roe deer (Capreolus capreolus).

Annual variations in concentrations of luteinizing hormone (LH) and testosterone in plasma were analysed in relation to the antler cycle in six adult male roe deer exposed to a natural photoperiod (latitude 46 degrees 10'N) and in four adult males maintained in a constant short-day photoperiod (8 h light: 16 h dark) for a year, from the winter solstice at which time both groups of animals had antlers in velvet. The animals were sampled, every 15 min for 2 or 4 h at intervals of one month for a year. Under both natural and experimental conditions, LH concentrations were high from January to March, but in the experimental conditions they decreased between April and May-June, whereas in the natural conditions they increased. Plasma LH concentration was lowest between July and November in animals under natural photoperiod, whereas under 8 h light:16 h dark photoperiod a second increase in plasma LH occurred between August and September. Between March and August, concentrations of plasma testosterone increased under natural photoperiod, whereas under experimental photoperiod there was a biphasic pattern of plasma testosterone with peaks between February and May and between September and November. Under natural photoperiod, antlers were cast in November, 369 +/- 6 days after the previous antlers were cast. Under experimental photoperiod, antlers were cast after 193 +/- 10 days, and a new set developed. The sexual cycle of the male appears to be initiated by an endogenous rhythm in winter and is then maintained by hormonal changes resulting from increasing photoperiod in spring.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Effect of exposure to long days on the secretion of oestradiol, oestrone, progesterone, testosterone, androstenedione, cortisol and follicle-stimulating hormone in intact and spayed ferrets.

The changes in concentration of plasma oestradiol, oestrone, progesterone, androstenedione, testosterone, cortisol and FSH were followed in intact female ferrets brought into oestrus by extension of the photoperiod from 8 to 16 h daily. An additional group of spayed females was similarly exposed to the extended photoperiod. There was no change in the blood oestrone, androstenedione and testosterone levels in the spayed females; the concentration of oestradiol, progesterone and FSH fell, while that of cortisol rose after 6 weeks. The intact females showed no change in plasma oestrone and cortisol concentrations, a rise in plasma oestradiol associated with the onset of oestrus, and falls in the blood levels of testosterone, androstenedione, progesterone and FSH. These results indicate that the changes in plasma gonadal steroid levels after extension of the photoperiod differ markedly from those in rodents or ruminants.

Androstenedione↗
PubMed1994

The effect of epitestosterone on gonadotrophin synthesis and secretion.

The effects of 3-week treatment with increasing doses of epitestosterone (ET) on gonadotrophin gene expression and secretion, on testosterone and 5 alpha-dihydrotestosterone (DHT) levels, and on the weight of testes and prostates, were studied in intact adult male rats. The hormones were delivered by means of silastic capsules of different lengths filled with the steroid. One group of rats received testosterone (T) instead of ET, to compare the results with previous studies concerning the testosterone effect. The controls were given capsules with glucose only. Treatment with ET, as well as with T, significantly reduced the weights of prostates. When the data from ET-treated rats and controls were combined, a significant negative correlation (P < 0.001) was found between the weight of prostates and serum ET. T, in contrast to ET, also decreased significantly the weights of testes, ET treatment caused a significant reduction of serum T levels but only an insignificant decline of DHT levels, independent of the dose. Serum and pituitary (p) luteinizing hormone (LH) levels in the ET-treated rats did not change. Pituitary mRNA contents for the beta LH subunit (beta LH-mRNA) showed a dose-dependent significant increase, up to 170% (P < 0.01), with ET treatment. pFSH decreased with the lowest ET (2 cm) dose (P < 0.05), but no change was observed with the other doses. The mRNA for the common alpha-subunit also increased with the ET load. In conclusion, ET acts at several sites in the regulation of gonadotrophin formation and release. It enhances the steady-state mRNA levels of both gonadotrophins in the pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Effects of melatonin in the mediobasal hypothalamus on the secretion of gonadotrophins in sheep: role of dopaminergic pathways.

Previous studies have shown that treatment with micro-implants of melatonin in the mediobasal hypothalamus (MBH) of sexually inactive Soay rams exposed to long days induces an increase in the secretion of FSH and reactivation of the testicular axis, as normally occurs in response to short days. The current study was conducted to investigate the possible involvement of hypothalamic dopaminergic (DA) systems in this melatonin-induced effect. At 10 weeks under long days, sexually inactive Soay rams were treated in the MBH with micro-implants containing bromocriptine (DA agonist) or sulpiride (DA antagonist), given alone or in combination with melatonin, to establish whether the DA drugs would mimic or negate the effects of melatonin. All micro-implants were inserted bilaterally and left in place for 14 weeks; the study lasted a total of 28 weeks (14 weeks implant period and 14 weeks post-implant period) while the animals remained under long days. The ability of the micro-implants to release bromocriptine and sulpiride for 14 weeks was confirmed by incubating implants in vitro and testing for the presence of the compounds in the incubate using a pituitary cell bioassay. Profiles of FSH, determined in blood samples collected three times weekly, were significantly different among treatments (time x treatment interaction, P < 0.001, ANOVA). Melatonin in the MBH induced a marked increase in the concentrations of FSH during the implant period, and a decrease during the post-implant period (P < 0.001). Bromocriptine given alone in the MBH induced a decrease in the concentrations of FSH which became statistically different from the control during the post-implant period (P < 0.05). Treatment with sulpiride alone also resulted in a suppressive effect during the post-implant period (P < 0.01). When given in combination with melatonin, bromocriptine or sulpiride significantly reduced the melatonin-induced increase in the concentrations of FSH observed during the implant period (P < 0.001). The results support the view that DA pathways in the MBH play an important role in the inhibitory regulation of gonadotrophin secretion in the ram. The inhibitory effect of bromocriptine is likely to result from the direct activation of the hypothalamic DA receptors linked to GnRH neurones regulating the secretion of FSH. The apparent paradoxical inhibitory effect of sulpiride is thought to be due to enhanced gonadal steroid negative feedback resulting from blockade of the inhibitory DA pathways, as evidenced by significantly increased secretion of testosterone (P < 0.05) in the animals receiving sulpiride in combination with melatonin.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

Urinary prostate-specific antigen is a noninvasive indicator of sexual development in male children.

Testicular androgen induces the synthesis of prostate specific antigen (PSA) in acinar epithelial cells of the prostate. We examined PSA activity in urine from 136 male children from birth up to 17 years of age. We detected PSA at various intervals in early infant urine over a period of 1-4 months. During this period, urinary secretion of testosterone (T) gradually declined, accompanied by 1 or more surges of T prior to a transient increase in PSA in urine from full- and preterm infants (67%, n = 6). Although mean urinary T concentrations during elevations of PSA in preterm infants were 3.1 and 5.6 times greater than in full-term infants and adults, the overall mean urinary PSA concentration of full and preterm infants was just 45% and 18% that of adults, respectively. PSA was not detected in children aged 0.3 to 9 years, after which a gradual increase in urinary PSA activity was observed after 10 years of age. Urinary PSA activity was markedly persistent after Tanner stage III pubertal development. To our knowledge, this is the first study to demonstrate an induction of PSA during early infancy by bioactive T in normally developing human males. We conclude that urinary PSA is a non-invasive, useful indicator for developmental studies from neonatal and adolescent males, which can be measured with a confirmatory semiquantitative PSA assay.

Adolescent↗