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Ilpo Huhtaniemi

Huhtaniemi I. Fetal testis—a very special endocrine organ. Eur J Endocrinol 1994;130:25–31. ISSN 0804–4643

The fetal testis is a special organ endocrinologically and not at all like a smaller version of the adult testis. Unlike the quiescent fetal ovary, its hormone production is very active. Besides testosterone it produces a special 'fetal gonadal hormone', the anti-Müllerian hormone. These two hormones together play a key role in the induction and regulation of male sexual differentiation. To meet these functional requirements the fetal testis has many unique features, especially as regards luteinizing hormone and follicle-stimulating hormone action, which discriminate it from the respective functions of the adult testis. In this article, some enigmatic features of fetal testicular endocrine function are concentrated on in an attempt to identify the most important questions for further research.

Ilpo Huhtaniemi, Department of Physiology, University of Turku, Kiinamyllynkatu 10,20520 Turku, Finland

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Ilpo Huhtaniemi

Every scientist finds it increasingly difficult to keep up with literature in the current flood of scientific information. Just following the literature is more than a full-time job. The computerized searching systems are becoming more and more valuable since these days nobody is able to scan personally through all the journals of interest. A narrow special field can still be followed in a comprehensive manner, but this will mean that the old cliché is becoming a reality that we know more and more about less and less.

What should be done? One way would be to reduce the amount of material published, but as the number of scientists today is larger than ever before there is bound to be more scientific literature as well. The other solution, which has to be done on an individual basis, is to reduce and refocus the material to read. Obviously, one has to follow

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Ilpo Huhtaniemi

ABSTRACT

The metabolism of pregnenolone and pregnenolone sulphate was studied in incubations with minced foetal liver tissue. In most of the incubations, non-radioactive substrates were used, and the identification and quantitative determination of the metabolites formed was carried out by gasliquid chromatography and gas chromatography – mass spectrometry. Both the free and sulphated substrates were extensively metabolized by the liver preparations, and with both substrates, the same enzyme activities were observed. Furthermore, active sulphate conjugation was seen with free pregnenolone. No sulphatase activity was observed, and the direct conversion of pregnenolone sulphate to 16α-hydroxypregnenolone sulphate was demonstrated in incubations with [7-3H]pregnenolone [35S]sulphate. The highest conversion rate with both substrates, about 25 %, was for 16α-hydroxylation. Other enzyme activities detected were 20α-reduction and 3β-hydroxy-5,16-pregnadien-20-one formation. In sulphate conjugation and 16α-hydroxylation a slight decrease was observed with advancing foetal age, while in the case of 20α-reduction, somewhat higher conversion rates were observed in older foetuses. In this respect, the only significant difference between the two substrates used was the more pronounced decrease in pregnenolone sulphate 16α-hydroxylation with increasing foetal age.

This study sheds more light on the biological significance of steroid sulphates as metabolic intermediates in the human foetus and further evidence for their direct conversion into other steroid sulphates was obtained. It is suggested that the foetal liver plays an active role in such conversions.

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Ilpo Huhtaniemi

The two pituitary gonadotrophins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and in particular LH-stimulated high intratesticular testosterone (ITT) concentration, are considered crucial for spermatogenesis. We have revisited these concepts in genetically modified mice, one being the LH receptor (R)-knockout mouse (LuRKO), the other a transgenic mouse expressing in Sertoli cells a highly constitutively active mutated Fshr (Fshr-CAM). It was found that full spermatogenesis was induced by exogenous testosterone treatment in LuRKO mice at doses that restored ITT concentration to a level corresponding to the normal circulating testosterone level in WT mice, ≈5 nmol/L, which is 1.4% of the normal high ITT concentration. When hypogonadal LuRKO and Fshr-CAM mice were crossed, the double-mutant mice with strong FSH signaling, but minimal testosterone production, showed near-normal spermatogenesis, even when their residual androgen action was blocked with the strong antiandrogen flutamide. In conclusion, our findings challenge two dogmas of the hormonal regulation of male fertility: (1) high ITT concentration is not necessary for spermatogenesis and (2) strong FSH stimulation can maintain spermatogenesis without testosterone. These findings have clinical relevance for the development of hormonal male contraception and for the treatment of idiopathic oligozoospermia.

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Iiris Salonen and Ilpo Huhtaniemi

Abstract. We studied the effects of one-week ethanol exposure (2.2 g/kg twice daily) on pituitary-gonadal functions of male rats. Because ethanol decreases the food-intake of the animals, diet-restricted rats were used as controls. Testicular LH and PRL receptors of ethanol-treated rats were significantly (P <0.05–0.01) reduced in comparison with weight-matched controls. In contrast, testicular GnRH receptors of the ethanol group were increased (P <0.05). Testicular FSH binding, pituitary GnRH-receptors, and serum gonadotropins and testosterone were not affected by ethanol. The present results demonstrate a specific effect of ethanol on testicular LH and PRL receptors which, unlike some other endocrine changes during ethanol expoure, is not due to a concomitant weight loss. In addition, the results suggest a concurrent change in the putative testicular GnRH receptor associated paracrine regulation, as implied by increased testicular GnRH binding upon ethanol exposure.

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Leo Dunkel and Ilpo Huhtaniemi

Abstract.

To investigate the role of gonadotropins in postnatal testicular activation, testosterone responsiveness to human chorionic gonadotropin was studied in 11 male infants (aged 5-180 days). The boys were given a single im injection of 5000 IU/1.7m2 hCG, and serum and salivary testosterone responses were then measured for 7 days. The results were compared with the serum testosterone responses of 8 older prepubertal boys (aged 1.7-10.4 years) studied with the same protocol. The mean (±sem) basal serum testosterone levels were 2.67±1.27 nmol/l in the infants and 0.09±0.02 nmol/l in the prepubertal boys (p<0.05). Both groups gave a significant response to hCG stimulation (p<0.001, ANOVA, one-way). The stimulated concentrations of serum testosterone were higher in the infants than in the prepubertal boys (p<0.001). The mean basal level of salivary testosterone was 30.5 ±7.0 and the mean maximal level was 97± 10.3 pmol/l in the infants (p<0.001). No age-related changes were observed in either basal or hCG-stimulated levels. In infants the mean (±sem) maximal hCG-stimulated increase was 25 ± 10-fold in serum and 8±4-fold in saliva (p=0.13). A clear stimulatory effect of hCG on testicular testosterone production was found, suggesting that the postnatal increase in serum testosterone concentration in male infants is gonadotropin-mediated. Salivary testosterone concentrations can be increased by hCG, indicating that measurements of salivary testosterone may provide an optional, non-invasive method for assessing gonadal function in children.

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Hannu Nikula and Ilpo Huhtaniemi

Abstract.

The role of protein kinase C in modulation of the endocrine function of rat Leydig cells was studied. Percoll-purified rat Leydig cells were stimulated with hCG, forskolin, cholera toxin, pertussis toxin and 8-bromo-cAMP in the presence and absence of two activators of protein kinase C, 12-0-tetradecanoylphorbol 13-acetate (TPA) or 1-oleoyl-2-acetyl-sn-glycerol (OAG). The two activators had no effect on basal cAMP, but decreased hCG-stimulated, and increased cholera toxinand forskolin-stimulated cAMP production. Cells pre-incubated with pertussis toxin showed enhanced rate of cAMP production in response to forskolin, but were no more responsive to TPA and OAG stimulation. These findings suggest that protein kinase C activation may on one hand inhibit the LH-receptor and Gs-protein coupling and on the other hand inhibit the Gi-protein mediated suppression of adenylyl cyclase activity. TPA and OAG effects on testosterone production were measured in the absence and presence of 8-bromo-cAMP stimulation. TPA enhanced basal testosterone production, but this effect was shifted to inhibition when steroidogenesis was stimulated by 8-bromo-cAMP. The OAG effect on testosterone production was inhibitory throughout the dose-response curve of 8-bromo-cAMP. The basal stimulation of testosterone production by TPA was probably due to a marginal increase of cAMP caused by inhibition of the Gi-protein, since a similar effect was observed by pertussis toxin, and therafter TPA was without effect on testosterone. The inhibition of stimulated testosterone production by TPA and OAG indicates that protein kinase C activity also affects steroidogenesis at a step(s) beyound cAMP formation.

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Ying-Qing Ding and Ilpo Huhtaniemi

Abstract.

The present study aimed at investigating the nature and causes of non-parallelism in testosterone responses to serial dilutions of peripheral serum and standard LH preparations in the mouse Leydig cell in vitro bioassay of LH. Immunoadsorption with monoclonal antibody to the β-subunit of LH was used to obtain LH-free serum; the procedure removed more than 98% of the immunoassayable LH. When a constant amount of the LH-free serum was added to standard dilutions, the bioassay dose-response curves to serum dilutions and standards became parallel, i.e. the well-known source of error of this assay system was eliminated. When standard curves prepared in medium and LH-free serum (final concentration 10%) were compared, no effect of the serum was found on basal cAMP and testosterone production. However, the LH-stimulated testosterone and cAMP production were suppressed by serum by a rather constant factor of 40%. Mild heating (60°C, 15 min) or treatment with dextran-coated charcoal, but not ether extraction, was able to eliminate the inhibitory activity of the LH-free serum. Binding studies demonstrated that [125I]hCG interaction with mouse Leydig cell homogenates was inhibited by LH-free serum in a fashion indicative of reduced LH receptor number, but not of reduced binding affinity. In conclusion, these data show that human serum contains LH inhibitor(s) which affect the LH-receptor interaction and LH stimulated testosterone production in mouse Leydig cell in vitro. The effect is marked in serum concentration over 1.5% and it shows only minor variation between individual sera. This source of error can be effectively removed from the LH in vitro bioassay by using LH-free serum for preparation of dilutions of LH standards.

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Erkki Pesonen, Pirkko Pussinen and Ilpo Huhtaniemi

Objective

The objective of this study was to explore whether circulating testosterone (T) concentration is associated with the occurrence and risk for acute coronary syndromes (ACS).

Method

This case–control study included male patients with acute myocardial infarction (AMI) (n=174) or unstable angina pectoris (UAP) (n=90) and healthy controls (n=238). Patients gave serum samples during the acute (n=264) and recovery (n=132) phases after a median of 10.5 months after the incident event. Secondary events (ACS or cardiovascular death) were registered during the following 6 years.

Results

During the acute phase, AMI and UAP patients had similar significantly reduced concentrations of serum testosterone in comparison to controls. Testosterone associated inversely with weight, the degree of inflammation (i.e. C-reactive protein concentration) and signs of a chronic infection. In a multiadjusted Cox regression, when compared to testosterone concentrations considered high-normal (14.91–34.0 nmol/l), low-normal testosterone (9.26–14.90 nmol/l) in the acute phase predicted better prognosis for cardiovascular death rate with a hazard ratio (HR) of 0.17 (0.04–0.68, P=0.012). The increased testosterone concentrations after the recovery period did not associate with future cardiovascular disease events.

Conclusion

Low-normal testosterone levels in the acute phase of ACS predicted better survival. The observation may indicate better adaptation to stress in survivors and warrants further study.

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Pirjo A Pakarinen and Ilpo T Huhtaniemi

The postnatal development of the gonadal negative feedback control of gonadotropins was studied in female rats. Neonatal (5-day-old) and randomly cycling young (60-day-old) and more mature (180-day-old) adult rats were ovariectomized, and half of them received Silastic implants containing the synthetic estrogen, diethylstilbestrol. The neonatal rats were killed 5, 10 or 15 days, and the adult rats 7 days after the operation. Age-matched and sham-operated animals served as controls. There were no statistically significant responses of serum LH or FSH concentrations or of the pituitary gonadotropin subunit mRNA levels to ovariectomy at any of the neonatal ages. A marked increase (p<0.01) after ovariectomy was seen in serum gonadotropins and in the cognate mRNA levels at both adult ages. In spite of the weak feedback response of the neonatal rats to ovariectomy, diethylstilbestrol suppressed the basal pituitary gonadotropin concentrations and the specific LH and FSH β-chain mRNAs (p<0.01–0.05). These results demonstrate that the gonadal negative feedback regulation of gonadotropin synthesis and secretion is not fully developed in neonatal and prepubertal female rats before 20 days of age. This is probably due to the steroidogenic quiescence of the ovaries in early life. However, the capability of the pituitary to respond to negative estrogen feedback has developed in the neonatal female, as demonstrated by the suppressive effects of diethylstilbestrol treatment on gonadotropin secretion.