[Synthesis of gonadotropins, their effects and the diseases linked to them].
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Follicle Stimulating Hormone↗
Biomedical subjects
I Huhtaniemi
Publications and source records attributed to I Huhtaniemi.
Genistein exerts estrogen-like effects in male mouse reproductive tract.
The aim of this study was to evaluate the estrogenicity of genistein in the neonatal and adult male mouse reproductive tract. In intact adults, genistein (2.5 mg s.c./kg of body weight/day for 9 days) reduced testicular and serum testosterone concentrations, pituitary LH-content and prostate weight. In castrated adults, genistein (0.025-2.5 mg s.c./kg of body weight) increased expression of c-fos gene in prostatic urethra. In adult, neonatally estrogenized mice showing an increased estrogen sensitivity, a 10-day treatment with genistein (2.5 mg s.c./kg of body weight) induced development of squamous epithelial metaplasia in prostatic collecting ducts. Neonatally, only a very high dose of genistein (1 mg/pup per day; i.e. approximately 500 mg/kg of body weight) induced persistent structural changes, similar to those seen in mice treated neonatally with diethylstilbestrol, in the urethroprostatic complex. These results suggest that in adult males, genistein induces the typical estrogenic effects in doses comparable to those present in soy-based diets, while in neonatal animals, considerably higher doses are required to show estrogen-like activity.
Aging↗
The unique exon 10 of the human luteinizing hormone receptor is necessary for expression of the receptor protein at the plasma membrane in the human luteinizing hormone receptor, but deleterious when inserted into the human follicle-stimulating hormone receptor.
The LH receptor (LHR) is a member of the family of G protein-coupled seven-times plasma membrane transversing receptors. Its gene consists of 11 exons, the last one encoding the transmembrane and intracellular domains of the receptor. The FSHR, and its gene, resemble structurally those of the LHR, with the exception that the sequences corresponding to exon 10 in LHR are missing in FSHR, which is thus encoded by a total of ten exons. Our recent studies on the marmoset monkey testis LHR cDNA indicated that an 81 bp nucleotide sequence, encoding the complete exon 10 of the LHR gene in other mammalian species, is absent in this species without affecting the LHR function. To study further the role of the exon 10 encoded sequences of the LHR in the gonadotropin receptor function, a deletion of exon 10 from the human LHR (hLHdeltaexon10R), and a chimeric hFSHR with exon 10 from hLHR inserted (hFSHLHexon10R), were constructed in expression vectors. The results presented here demonstrate that 293 cells transfected with the hLHdeltaexon10R display a decrease in the proportion of the receptor binding at the cell surface, compared with cells transfected with wild-type hLHR. However, the cells expressing hLHdeltaexon10R showed similar high affinity binding of [125I]iodo-hCG as those transfected with wild-type hLHR, in either intact cells or their detergent extracts. In addition, cells expressing the hLHdeltaexon10R and wild-type hLHR displayed similar dose-response of cAMP production to hCG stimulation. Cells transfected with chimeric hFSHLHexon10R showed barely detectable [125I]iodo-FSH binding in intact cells compared with those transfected with wild-type hFSHR. The FSH binding detected in cellular detergent extracts displayed 10-fold lower binding activity than wild-type receptors, in spite of similar level of immunoreactive FSHR protein expression in the transfected cells. The hFSHLHexon10R had a modest 5-fold lower binding affinity for FSH as compared with wild-type hFSHR. In conclusion, the present study indicates that the sequences encoding exon 10 of the hLHR are essential for the LHR expression at the plasma membrane, but deleterious for function if inserted into the hFSHR.
Animals↗
Vasoactive intestinal peptide stimulates testosterone production by cultured fetal rat testicular cells.
As a part of a series of studies on the regulation of testicular steroidogenesis in the fetal rat, we found that VIP stimulated fetal testicular cAMP production at a dose of 10(-9) mol/l, while a dose as low as 10(-12) mol/l stimulated testosterone production. RT-PCR analysis could not reveal either VIP mRNA in fetal tissues or VIP1 receptor mRNA in the fetal or newborn testes, while VIP2 receptor mRNA was detected testes as early as E15.5. The testicular VIP content was unmeasurable by our radioimmunoassay method ( < 1 fmol/testis), while the circulating levels of VIP were 82.9+/-1.1 pmol/l at E17.5 and decreased with advanced fetal ages. In conclusion, our results suggest that VIP, from and extratesticular source, may regulate fetal testicular steroidogenesis through type 2 receptors as early as E15.5.
Animals↗
Stable transfection of the rat follicle-stimulating hormone receptor complementary DNA into an immortalized murine Sertoli cell line.
A plasmid expressing the rat FSH receptor (R) cDNA under the Simian virus (SV) 40 promoter/enhancer was stably transfected into a mouse Sertoli cell (SC) line (MSC-1) established from transgenic mice carrying a fusion gene of the human anti-Müllerian hormone (AMH) promoter sequences linked to the SV40 T-antigen gene (Peschon et al., 1992). The original cell line has numerous SC characteristics, but it was reported not to express the inhibin-alpha and follicle-stimulating hormone (FSH)R genes. The new FSHR expressing cell line possessed approximately 2000 per cell with equilibrium association constant (Ka) of 1.5 x 10(9) l/mol. In Northern blots, an FSHR mRNA species of 2.6 kb was found. The cells responded to recombinant human FSH (recFSH) and pertussis toxin (PT) with stimulated cAMP production. Moreover, PT enhanced the FSH-stimulated cAMP production in these cells, indicating the presence of a functional Gi protein. 12-O-tetradecanoylphorbol-13-acetate (TPA) suppressed the FSH-stimulated cAMP production of the cells, which effect was similar to that observed previously upon protein kinase C (PKC) activation in rat seminiferous tubules in vitro. Hence, the FSHR signalling, and its modulatory pathways, were intact in the FSHR expressing MSC-1 cell line. RT-PCR with inhibin-alpha specific oligonucleotide primers. followed by Southern hybridization, indicated that, unlike previously shown, the original and the FSHR expressing MSC-1 cells do express the inhibin alpha gene. FSH stimulation of the cells decreased their proliferation and, unexpectedly, the inhibin-alpha mRNA levels. The cells have functional features both from neonatal and mature SC. A feature of the former cells is the lack of FSH-stimulated up-regulation of inhibin-alpha expression; in fact FSH decreased this message. The antiproliferative, and apparently differentiating, effect of FSH on these cells resembled mature SC functions. Since adult SC do not proliferate in vitro, the new FSHR expressing and proliferating cell line provides a useful in vitro model for studying some facets of SC functions, though keeping in mind that these transformed cells do not behave identically with adult SC in vivo. The constitutive expression of FSHR in these cells allows the study of posttranscriptional events in the FSHR regulation.
Animals↗
Receptors for anti-müllerian hormone on Leydig cells are responsible for its effects on steroidogenesis and cell differentiation.
Strong overexpression of anti-Müllerian hormone (AMH) in transgenic mice leads to incomplete fetal virilization and decreased serum testosterone in the adult. Conversely, AMH-deficient mice exhibit Leydig cell hyperplasia. To probe the mechanism of action of AMH on Leydig cell steroidogenesis, we have studied the expression of mRNA for steroidogenic proteins in vivo and in vitro and performed a morphometric analysis of testicular tissue in mice overexpressing the hormone. We show that overexpression of AMH in male transgenic mice blocks the differentiation of Leydig cell precursors. Expression of steroidogenic protein mRNAs, mainly cytochrome P450 17 alpha-hydroxylase/C17-20 lyase (P450c17), is decreased in transgenic mice overexpressing AMH and in AMH-treated purified Leydig cells. In contrast, transgenic mice in whom the AMH locus has been disrupted show increase expression of P450c17. In vitro, but not in vivo, AMH also decreases the expression of the luteinizing hormone receptor. The effect of AMH is explained by the presence of its receptor on Leydig cells. Our results provide insight into the action of AMH as a negative modulator of Leydig cell differentiation and function.
Animals↗
Progesterone can participate in down-regulation of the luteinizing hormone receptor gene expression and function in cultured murine Leydig cells.
The intratesticular concentration of progesterone (P) rises up to the micromolar range during high-dose luteinizing hormone (LH)/hCG stimulation. The aim of this study was to examine whether P is involved in the concomitant down-regulation of the LH receptor (R) function. The effects were tested in a mouse Leydig tumor cell line (mLTC-1) and in Percoll-purified adult mouse Leydig cells. Pre-incubation of the mLTC-1 cells for 48 h with P (1-10 micromol/l) decreased in dose-dependent fashion their specific binding of [125I]iodo-hCG as well as the hCG-induced cAMP production (down to 65 and 40% respectively, of controls, P < 0.01). Similar effect of P on hCG-induced cAMP production was observed in adult mouse Leydig cells following a 24 h incubation in the presence of P (0.3-10 micromol/l). In addition, P treatment significantly inhibited the expression of a transiently transfected murine LHR promoter (715 or 950 bp of the 5' untranslated region)-luciferase fusion constructs in mLTC-1 cells (down to 50% of control, P < 0.01). In accordance, a 6-12 h culture in the presence of 5-10 micromol/l of P showed significant down-regulatory effects on the steady state levels of LHR-mRNA in mLTC-1 cells. These inhibitory effects of P on the LHR expression and function were mimicked by similar concentrations of cortisol, but not by testosterone or estradiol. Blocking the steroid synthesis of mLTC-1 cells with 86 micromol/l of aminoglutethimide (AMG) partially reversed the down-regulating effect of hCG on the LHR-mRNA. Moreover, a 24 h culture in the presence of AMG showed an up-regulating effect on expression of the LHR promoter-luciferase constructs, and including hCG (50 microg/l) in the culture medium enhanced this effect. Hence, in the absence of steroidogenesis, hCG up-regulates the LHR promoter expression. In conclusion, we present here a novel short-loop regulatory mechanism in murine Leydig cells where P exerts a negative effect on LHR expression and function. Since Leydig cell P production is dramatically increased during high-dose stimulation with LH/hCG, due to blockade of C21 steroid side chain cleavage, the present findings offer a function for this steroid in the LHR down-regulation.
Aminoglutethimide↗
Mutations and polymorphisms in the gonadotrophin genes; clinical relevance.
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Animals↗
Determination of a common genetic variant of luteinizing hormone using DNA hybridization and immunoassays.
OBJECTIVE: An immunologically anomalous form of LH, due to two point mutations in codons 8 and 15 of the LH beta gene, has previously been described. LH status, i.e. the discrimination between wild-type (WT) and variant (V) LH, is usually determined by immunoassays, which can be unreliable at low serum concentrations of LH. A DNA hybridization assay was therefore developed to score the LH genotype in all subjects, independent of their serum LH concentrations. To evaluate the performance of the hybridization method, and to expand our observations of the worldwide occurrence of the V-LH, we determined its frequency in additional populations. To confirm the connection between the anomalous immunoreactivity and the V-LH beta gene, we also sequenced the LH beta subunit gene of a homozygous person. DESIGN: According to the ratio of two immunoassays, one detecting only WT-LH and the other detecting equally WT and V-LH, individuals can be classified as homozygotes for the V-LH beta allele, heterozygotes or WT. DNA samples from persons with known LH status, according to the immunoassays, were used for the development and evaluation of a new allele-specific DNA hybridization assay. This assay, and PCR and restriction fragment length polymorphism analysis, were used to determine the frequency of the V-LH beta allele in DNA samples obtained from eight populations. PATIENTS: Ambulatory adult men and women, apparently healthy and with no endocrine disorders. RESULTS: The LH genotyping by immunoassays and by the new hybridization method gave identical results with all samples analysed (n = 25). The V-LH beta subunit was observed to always have the two point mutations, and to be identical with the ones previously reported. The V-LH beta carrier frequency in the DNA samples collected from various populations varied between 0 and 53.5%. CONCLUSIONS: The immunoassay technique and the hybridization assay can be used as alternatives to determine the LH status. A great variation in carrier frequency of the V-LH beta allele is observed in different populations.
Adult↗
Regulation of luteinizing hormone receptor gene expression by insulin-like growth factor-I in an immortalized murine Leydig tumor cell line (BLT-1)
It is postulated that insulin-like growth factor-I (IGF-I), a 70-amino acid mitogenic polypeptide, regulates Leydig cell steroidogenesis. In the present study, we assessed the effect of IGF-I on LH receptor (LHR) gene expression in an immortalized murine Leydig tumor cell line (BLT-1). Culture of BLT-1 cells in the presence of IGF-I (0.1-100 ng/ml) for 24 or 48 h increased their [125I]iodo-hCG binding in a dose-dependent manner up to 275% of the control level. Northern hybridization analysis revealed four major transcripts of LHR mRNA in BLT-1 cells (6.9, 2.6, 1.7, and 1.2 kilobases), and treatment at 10-100 ng/ml of IGF-I increased steady-state levels of LHR mRNAs in coordinate fashion up to 2. 2-fold. IGF-I (30 ng/ml) induced a time-dependent increase in [125I]hCG binding after a lag period of 2-6 h when studied up to 48 h, with a subsequent decrease. A similar response with steady increase up to 72 h was observed in total LHR mRNA. To elucidate the molecular mechanism of IGF-I action on LHR mRNA expression, we measured the transcription rate of the LHR gene by nuclear run-off assay and assessed transcript stability by the actinomycin D blocking method. The results showed that IGF-I treatment had no effect on the transcription rate of the LHR gene, whereas the half-life (t1/2) of LHR mRNA was significantly prolonged (IGF-I-treated cells, 30 +/- 3.8 h; controls, 17 +/- 2.5 h). Furthermore, IGF-I at 30 ng/ml and 100 ng/ml increased the expression of LHR promoter-driven luciferase and cytomegalovirus-promoter driven ss-galactosidase activities in BLT-1 cells; however, the former increased only marginally more than the latter. This suggests that the increase of LHR mRNA by IGF-I in Leydig cells is mainly due to increased mRNA stability.
Animals↗
Genetic variant of luteinizing hormone in women with a history of recurrent miscarriage.
Because the biological and clinical significance of a genetic variant of luteinizing hormone (LH) is unclear, we therefore evaluated the occurrence of variant LH in women with a history of recurrent spontaneous abortion (RSA) and related it to specific LH concentrations, luteal function and pregnancy outcome. Of the 85 RSA women, 30 (35.3%) had variant LH (28 heterozygous and two homozygous), and 55 women (64.7%) a normal wild-type LH ratio. These frequencies are similar to those reported from the general Finnish population. No significant differences were observed in specific LH concentrations based on LH status (7.2+/-1.4 IU/l, mean +/- SEM, variant LH, versus 8.5+/-1.6 IU/l, wild-type LH). Variant LH was twice as common in women with body mass index (BMI) > 25 kg/m2 (9/15, 60.0%) than in those with BMI < or =25 kg/m2 (21/70, 30.0%, P < 0.05). The presence of variant LH was not associated with any clear effect on endocrine variables such as endometrial maturation or mid-luteal phase oestradiol and progesterone concentrations. During follow-up, 23 women with variant LH (76.7 %) and 41 with wild-type LH (74.5%) became pregnant: 14 miscarried (21.9%, six with variant LH and eight with wild-type LH) and two had ectopic pregnancies, whereas 48 (75.0%) succeeded (17 with variant LH and 31 with wild-type LH). LH concentrations before pregnancy were similar in women with a successful outcome (8.0+/-1.3 IU/l) or with a miscarriage also in that pregnancy (7.4+/-1.4 IU/l). In conclusion, variant LH is common in RSA women who are relatively overweight (BMI > 25 kg/m2) but its presence is not reflected in endometrial maturation and miscarriage rates.
Abortion, Habitual↗
Gonadotropin-independent regulation of steroidogenesis in the fetal rat testis.
UNLABELLED: The goal of the present study was to determine whether the onset of fetal Leydig cell steroidogenesis is dependent on gonadotropic stimulation. The relationships between the onset of pituitary LH synthesis and secretion, and the response of testicular steroidogenesis to LH and various putative paracrine factors were examined. We found by reverse transcription-polymerase chain reaction (RT-PCR) that the LHbeta-subunit gene expression in the fetal pituitary gland starts on embryonic day (E) 16.5. Plasma LH was very low (< 5.0 ng/L) until E19.5 and increased significantly thereafter. In contrast, the greatest increase in the testicular testosterone had already occurred between E18.5 and E19.5. Hence, fetal testicular steroidogenesis must start independent of LH stimulation. Basal testosterone production in incubations of fetal testis (E16.5-19.5) was high, 50-80% of the hCG-stimulated level. In contrast, in dispersed fetal Leydig cells, basal steroidogenesis was consistently low. This suggests the presence of paracrine factors in the intact testes that stimulate their steroidogenesis. Effects of various putative paracrine factors were thereafter tested on the fetal testis. We found for the first time that both vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP-27) markedly stimulated fetal, but not adult, Leydig cells. IN CONCLUSION: 1) Pituitary LH cannot be the initial stimulus for fetal testicular steroidogenesis. 2) Some paracrine factor(s) probably turn on and maintain early fetal testicular steroidogenesis before the later onset of LH secretion, although a constitutive component in the onset of steroidogenesis is also possible. 3) VIP and PACAP-27 are likely candidates for a paracrine stimulus of the fetal testis.
Animals↗
Dose and time relationships of intravenously injected rat recombinant luteinizing hormone and testicular testosterone secretion in the male Rat.
The ability of hCG and LH to induce testosterone (T) secretion by Leydig cells is well documented. However, the influence of the pulsatile nature of LH secretion, with varying frequency and amplitude, on T production in vivo is less clear. In our earlier studies on the relationship between pulsatile LH release and T secretion in adult male rats, no simple causality was observed. The recent availability of rat recombinant (rec) LH prompted us to study the effects of one and of three i.v. pulses of different doses of rat recLH on T secretion in adult male rats rendered hypogonadotropic by treatment with the GnRH antagonist cetrorelix. One or three supraphysiological pulses of 1.0 microg of rat recLH produced similar maximal T responses. In contrast, high physiological LH pulses (0.1 microg) produced discrete T-response peaks, whereas multiple low pulses of LH (0.03 microg) were needed before a T response was achieved. The T stimulation was greatly diminished after an LH pulse of 0.1 microg if rats had been treated on the previous day with pulses of 0.03 vs. 0.1 microg rat recLH, apparently because of prolonged LH deprivation and lack of Leydig cell priming due to the GnRH antagonist treatment. The novel preparation of rat recLH provides a physiologically relevant tool for studying the complex relationship between pulsatile LH release and T secretion in male rats.
Animals↗
Fetal development of Leydig cell activity in the mouse is independent of pituitary gonadotroph function.
During fetal development the testes secrete anti-Mullerian hormone and testosterone to induce formation of the male phenotype. Adult Leydig cells secrete testosterone under the control of LH, but the role of the fetal pituitary in regulating fetal Leydig cell function is unclear. To study the early relationship between pituitary and Leydig cell function, we have examined the development of fetal pituitary LH levels and Leydig cell function in normal mice and in hypogonadal (hpg) mice that lack GnRH and, thus, circulating gonadotropins. In normal and hpg mice, pituitary LH content was barely detectable until embryonic day 17 (E17), when levels began to increase significantly in both groups. Pituitary levels of LH in hpg mice were, however, only about 10% of normal at all ages. Full-length LH receptor transcripts were first detectable in fetal testes on E16 in both normal and hpg mice. In normal mice, levels of testicular messenger RNA (mRNA) encoding cytochrome P450 side-chain cleavage and 17alpha-hydroxylase increased from E13 to reach a peak around birth. In hpg mice, levels of mRNA encoding these enzymes were normal until around birth, at which time there was a significant decline. Levels of testicular mRNA encoding 3beta-hydroxysteroid dehydrogenase type I were similar in normal and hpg mice and showed little change during development. Intratesticular testosterone reached a peak on E18 in normal animals before declining again after birth. In hpg mice, intratesticular testosterone levels were normal throughout fetal development and on the day of birth, but were barely detectable by postnatal day 5. Results show 1) that fetal Leydig cell function in the mouse is normal in the absence of endogenous circulating gonadotropins; 2) that Leydig cells become dependent on gonadotropins shortly after birth; and 3) that pituitary LH synthesis can start in the absence of GnRH but is dependent on LH for a normal level of synthesis and secretion.
Animals↗
Vasoactive intestinal peptide is an important endocrine regulatory factor of fetal rat testicular steroidogenesis.
This study elaborates our recent preliminary finding that vasoactive intestinal peptide (VIP) has a specific stimulatory effect on fetal rat Leydig cells. We examined the dose-response relationship for the effect of VIP on cAMP and testosterone production by dispersed fetal Leydig cells isolated from rat testes on embryonic day (E) 18.5. Further, we used RT-PCR to examine the expression of the VIP gene in fetal brain and testes and that of the VIP receptor genes in fetal testes and used RIA to measure VIP in testes and plasma during the fetal period. VIP stimulated fetal testicular cAMP production at a dose of 10(-9) mol/liter, whereas a dose as low as 10(-12) mol/liter stimulated testosterone production. This suggests that VIP at low doses may stimulate testosterone production using second messenger pathways other than cAMP. RT-PCR analysis could not reveal either VIP messenger RNA (mRNA) in fetal tissues or VIP1 receptor mRNA in the fetal or newborn testes, whereas VIP2 receptor mRNA was detected in fetal testes as early as E15.5. Northern hybridization analysis showed that the level of expression of VIP2 receptor mRNA is very low in fetal and neonatal testes and increases with age. The testicular VIP content was unmeasurable by our RIA method (i.e. <1 fmol/testis), whereas the circulating level of VIP was 82.9 +/- 1.1 pmol/liter on E17.5 and decreased with advancing fetal age. In conclusion, our results suggest that VIP from an extratesticular source, possibly from the maternal compartment, may regulate fetal testicular steroidogenesis through type 2 receptors as early as E15.5. These findings may be of physiological significance, because the onset of fetal testicular steroidogenesis occurs at an age (E15.5-19.5) before the onset of pituitary LH secretion.
Animals↗
The frequency of an inactivating point mutation (566C-->T) of the human follicle-stimulating hormone receptor gene in four populations using allele-specific hybridization and time-resolved fluorometry.
We have described previously in the Finnish population an inactivating point mutation (566C-->T) in the human FSH receptor (FSHR) gene. In women, this mutation causes hypergonadotropic ovarian failure with arrest of follicular maturation and infertility, whereas in men, there is variable suppression of spermatogenesis, but no absolute infertility. To determine whether the same FSHR mutation occurs in other populations, its frequency was determined in Finland, Switzerland, Denmark, and the Chinese population of Singapore. The mutation was screened for using genomic DNA extracted from whole blood or dried blood spots. Exon 7 of the FSHR gene was first amplified using a pair of biotinylated primers. The PCR products were then immobilized on streptavidin-coated microtitration wells and hybridized using short allele-specific oligonucleotide probes labeled with europium. Time-resolved fluorometry was used for europium signal detection. To test the reliability of this method, 40 isolated DNA samples and 35 dried blood spot samples were blindly tested for the 566C-->T FSHR mutation. The analyses yielded identical results with denaturing gradient gel electrophoresis and allele-specific restriction enzyme digestion of the same samples, thus demonstrating the reliability of the tested method. Automation of this procedure allows the screening of large numbers of samples, which was subsequently carried out to investigate the frequency of the 566C-->T mutation in the study populations. A total of 4981 samples from the above-mentioned 4 countries were analyzed. The frequency of the 566C-->T mutation was 0.96% for all Finnish samples (n=1976), with a strong enrichment of the mutant allele in the northeastern part of the country. Only 1 mutation carrier was identified in the samples from Switzerland (n=1162), whereas none was found in samples from Denmark (n=1094) and the Singapore Chinese (n=540). These results suggest that the 566C-->T mutation of the FSHR gene is enriched in Finland, but is uncommon in other populations.
Alleles↗
Inverse correlation between serum testosterone and leptin in men.
Besides its role in the regulation of energy balance, leptin seems to be involved in linking energy stores to the reproductive system. A gender-dependent difference exists in plasma leptin concentration and leptin messenger ribonucleic acid expression in rodents and humans. This difference does not seem to be explained simply by differences in the amount of body fat between genders. To elucidate the relationship of endogenous testosterone and leptin, we studied the serum leptin concentrations in 269 elderly nondiabetic men. In addition, to assess whether exogenously administered testosterone could influence leptin production, we followed the serum levels of leptin in 10 healthy men during a 12-month treatment with 200 mg testosterone enanthate, i.m., weekly for contraceptive purposes. We found that the serum leptin concentration correlated inversely (r = -0.39; P < 0.001) with that of testosterone in elderly men. This inverse correlation was still present when body mass index and plasma insulin were included in the analysis. The administration of testosterone to young men suppressed serum leptin from the pretreatment level of 3.4 +/- 1.4 to 1.9 +/- 0.6 micrograms/L during the therapy. After cessation of testosterone injections, serum leptin concentration returned back to the pretreatment level. It is concluded that testosterone has a suppressive effect on leptin production, as reflected by circulating levels of this hormone.
Adult↗
Direct luteinizing hormone action triggers adrenocortical tumorigenesis in castrated mice transgenic for the murine inhibin alpha-subunit promoter/simian virus 40 T-antigen fusion gene.
Transgenic (TG) mice, expressing the Simian Virus 40 T-antigen (Tag) under a 6-kb fragment of the murine inhibin alpha-subunit promoter (inh alpha p), develop gonadal tumors of granulosa/theca or Leydig cell origin. We showed previously that adrenocortical tumors develop if the TG mice are gonadectomized but never develop in intact animals. However, if functional gonadectomy was induced by GnRH antagonist treatment or by cross-breeding the TG mice into the hypogonadotropic hpg genetic background, neither gonadal nor adrenal tumors appeared. Since the most obvious difference between the gonadectomized and GnRH-antagonist-treated or Tag/hpg double mutant mice is the elevated gonadotropin secretion in the first group, we examined whether the adrenal tumorigenesis would be gonadotropin-dependent. Surprisingly, both the adrenal tumors and a cell line (C alpha 1) derived from one of them expressed highly functional LH receptors (LHR), as assessed by Northern hybridization, immunocytochemistry, ligand binding, and human CG (hCG)-stimulated cAMP and steroid production. No FSH receptor expression was found in the adrenal tumors by RT-PCR. hCG treatment of the C alpha 1 cells stimulated their proliferation, as measured by [3H]thymidine incorporation. This effect was related to hCG-stimulated steroidogenesis since progesterone, testosterone, and estradiol, at physiological concentrations, also stimulated the C alpha 1 cell proliferation. Different adrenocortical cells expressed initially LHR and Tag, whereas both were highly expressed in the tumor cells. In conclusion, the high level of functional LHR in the adrenal tumors indicates that this receptor can function as tumor promoter when ectopically expressed and stimulated by the ligand hormone.
Adrenal Cortex Neoplasms↗