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Biomedical subjects

P Licht

Publications and source records attributed to P Licht.

At least 19 recordsLinked to original sources
PubMed2007

Treatment of hereditary angioneurotic oedema (HANE) with tibolone.

OBJECTIVE: Eight women, aged 25-58 years, with hereditary angioneurotic oedema (HANE) were treated with tibolone, a synthetic steroid exhibiting oestrogenic, androgenic and progestational activity. DESIGN: Pilot study. RESULTS: Tibolone at a dose of 2.5-7.5 mg/day significantly reduced the number and severity of attacks and the number of ampoules of C1-esterase inhibitor (C1-INH) needed for symptomatic therapy. The efficacy of tibolone was comparable to that of danazol, while the androgenic side-effects were considerably reduced. CONCLUSIONS: Tibolone may represent an alternative to danazol administration for the prophylaxis of HANE in women.

Adult↗
PubMed2002

Exposure to naturally circulating androgens during foetal life incurs direct reproductive costs in female spotted hyenas, but is prerequisite for male mating.

Among all extant mammals, only the female spotted hyena (Crocuta crocuta) mates and gives birth through the tip of a peniform clitoris. Clitoral morphology is modulated by foetal exposure to endogenous, maternal androgens. First births through this organ are prolonged and remarkably difficult, often causing death in neonates. Additionally, mating poses a mechanical challenge for males, as they must reach an anterior position on the female's abdomen and then achieve entry at the site of the retracted clitoris. Here, we report that interfering with the actions of androgens prenatally permanently modifies hyena urogenital anatomy, facilitating subsequent parturition in nulliparous females who, thereby, produce live cubs. By contrast, comparable, permanent anatomical changes in males probably preclude reproduction, as exposure to prenatal anti-androgens produces a penis that is too short and has the wrong shape necessary for insertion during copulation. These data demonstrate that the reproductive costs of clitoral delivery result from exposure of the female foetus to naturally circulating androgens. Moreover, the same androgens that render an extremely unusual and laborious process even more reproductively costly in the female are apparently essential to the male's physical ability to reproduce with a normally masculinized female.

Androgen Antagonists↗
PubMed2002

VEGF plasma pattern in ovulation induction: evidence for an episodic secretion and lack of immediate effect of hCG.

Vascular endothelial growth factor (VEGF) is a potent stimulator of vascular proliferation and permeability. Ovarian granulosa cells have been identified as a major source of the cytokine and r-hCG was able to stimulate VEGF mRNA expression in vitro. In this study we have investigated the immediate effect of ovulation induction with hCG on peripheral VEGF levels in 6 women with primary infertility enrolled in the IVF/ET program. The patients underwent a 24-hour continuous blood withdrawal with sampling intervals of 15 minutes starting from 5 hours before ovulation induction with 10.000 IU hCG. Ovulation induction with hCG had no significant immediate effect on mean peripheral VEGF levels. However, VEGF plasma levels did exhibit significant episodic fluctuations with rapid increases every 90-120 minutes without any relation to circulating hCG levels. Taken together, the results of this study suggest that VEGF is released episodically and that systemic VEGF levels are not acutely altered by ovulation induction with hCG.

17-alpha-Hydroxyprogesterone↗
PubMed2001

On the role of human chorionic gonadotropin (hCG) in the embryo-endometrial microenvironment: implications for differentiation and implantation.

Recent evidence suggests that human chorionic gonadotropin (hCG), in addition to its well-known endocrine effects on the corpus luteum, may act as a growth and differentiation factor during pregnancy. According to experimental results, its mode of action may be divided into three sequential phases. During the first phase, which begins at the blastocyst stage and lasts until the occurrence in the serum, hCG acts preferentially in a juxtacrine manner. We have used an intrauterine microdialysis system developed in our laboratory to administer low concentrations of hCG to the endometrium of women in the luteal phase of the menstrual cycle. HCG administration provoked profound effects on paracrine parameters of differentiation (IGFBP-1, prolactin) and implantation (LIF, M-CSF). VEGF, a cytokine important for neoangiogenesis, was significantly stimulated by hCG (P < .01), suggesting a role for hCG in the control of endometrial vascularization and placentation. The investigation of endometrial parameters of tissue remodeling revealed a significant increase of MMP-9 (P < .05) but not of TIMP-1 following hCG infusion. The second, endocrine, phase of hCG action is marked by the appearance of hCG in the maternal serum. Rising systemic hCG levels cause a very rapid elevation of serum progesterone reflecting the rescue of the corpus luteum. Other endocrine functions of hCG include its intrinsic thyrotropic activity as well as modulation of fetal testicular, ovarian, and adrenal function. The third phase may be characterized by the expression of full-length hCG/LH receptors on the trophoblasts themselves. Before the ninth week of gestation, human villous trophoblasts express a truncated hCG/LH receptor isoform (50 kDa) and are probably not responsive to hCG. Later, the expression pattern is switched to the full-length receptor (80 kDa), allowing hCG also to modulate the differentiation of the trophoblasts themselves. A special feature is the self-regulation of hCG biosynthesis that may in part explain the unique secretion profile of the hormone with peak levels during the first trimester followed by a rapid decline after the tenth week of gestation. In summary, hCG seems to have a variety of local and systemic functions in and outside the embryo-endometrial microenvironment.

Cell Differentiation↗
PubMed2001

Peripheral levels of vascular endothelial growth factor (VEGF) are higher in gonadotropin stimulated as compared to natural ovarian cycles.

The purpose of the present study was to investigate the stability of vascular endothelial growth factor (VEGF) in plasma samples and the influence of ovarian hyperstimulation on systemic levels of VEGF. Stability assays for VEGF in plasma samples revealed significant increases following even short incubations of samples at room temperature (< or = 2 h, p < 0.001). To investigate a possible impact of controlled ovarian hyperstimulation (COH) on peripheral VEGF levels, serial blood collection over one menstrual cycle was performed in unstimulated as well as in gonadotropin-stimulated cycles for in vitro fertilisation/embryo transfer (IVF/ET) (10 women each). Peripheral levels for VEGF were significantly higher in gonadotropin stimulated cycles as compared to non-stimulated cycles (p < 0.001). There was no significant difference between follicular phase and luteal phase levels in either group. VEGF levels tended to correlate with the number of follicles detected by vaginal sonography prior to oocyte aspiration (p = 0.051). In conclusion, VEGF levels are elevated in gonadotropin-stimulated IVF/ET cycles as compared to natural cycles.

Chorionic Gonadotropin↗
PubMed2001

Molecular aspects of direct LH/hCG effects on human endometrium--lessons from intrauterine microdialysis in the human female in vivo.

The regulation of human implantation is still unknown. Evidence derived from experiments in vitro and from animal systems suggest a direct impact of the embryo on endometrial differentiation and the implantation process itself. Being one of the earliest embryonic products, hCG may be a key mediator of this embryo-maternal communication. Using a multiplex nested rT-PCR approach we have been able to demonstrate the presence of full-length and truncated hCG/LH-receptor mRNA in human endometrium and in decidua. The expression of functional receptors appears to be cycle-dependent and regulated by changes in the alternative splicing pattern. To investigate possible direct effects of hCG on endometrial paracrinology in the human female in vivo, we have developed an intrauterine microdialysis system that allows the continuous sampling from the uterine cavity over several hours as well as the application of exogenous hCG and the monitoring of the tissue response to this stimulus. HCG administration during the secretory phase significantly modulated several endometrial paracrine parameters that correlate to endometrial differentiation (IGFBP-1), angiogenesis (VEGF), implantation (LIF, M-CSF) and tissue remodelling (MMP-9). In summary, intrauterine microdialysis is a novel tool for the clinical assessment of endometrial paracrinology in vivo. HCG appears to directly modulate endometrial differentiation and function in humans.

Alternative Splicing↗
PubMed2000

Widespread expression of the mRNA encoding a novel vitamin D/thyroxine dual binding protein in the turtle Trachemys scripta.

Vitamin D-binding protein (DBP) is the major transport protein for the vitamin D sterols in a variety of mammalian and avian species. The DBP found in the emydid family of turtles is unique in that it exhibits high-affinity binding of both vitamin D and thyroxine (D/TBP). Sequence analysis has revealed that the emydid D/TBP is homologous to mammalian DBP and shares no homology with mammalian thyroxine-binding globulins. Northern blot analysis was used to examine the spatial profile of D/TBP transcription in the turtle Trachemys scripta. In both adults and hatchlings, two transcripts--the expected 1.5-kb full-length transcript and a second 0.8-kb transcript--were present in nearly all of the tissues examined. In adults, highest expression of the 1.5-kb transcript was seen in the kidney, gonad, and spleen, with lower levels in the liver and lung and no transcripts in skeletal muscle. In hatchlings, the full-length transcript was detected in a variety of tissues at similar levels. Injection of hatchlings with thyroxine increased levels of circulating D/TBP and transcript levels. These data are in marked contrast to observations in mammals in which transcription of DBP is confined predominantly to the liver. Further, the increase in circulating D/TBP associated with increased thyroidal activity may result from a direct or indirect activation of D/TBP transcription by thyroxine.

Aging↗
PubMed1999

Characterization of thyroid hormone 5'-monodeiodinase activity in the turtle (Trachemys scripta).

Thyroid hormone metabolism by 5'-monodeiodinase enzymes (5'MD) was characterized in peripheral tissues of the turtle, Trachemys scripta, and compared with activity measured in the rat. Based on differences in pH dependence, sensitivity to inhibitors, substrate affinity, and cofactor requirements, at least two types of enzyme activities have been identified in the turtle. A 5'MD activity was measured in liver and kidney microsomal fractions that exhibits inhibition by 2n-propyl-6-thiouracil (PTU), a higher affinity for rT3 (Km = 2 microM) than for T4 (Km = 6.5 microM), a low cofactor dependence, and a high pH optimum for T4 metabolism. The characteristics of this turtle low affinity T4 activity correspond to the mammalian type I monodeiodinase. A second type of monodeiodinase (MD) activity that is less sensitive to PTU, has a higher affinity for T4 (Km = 1 nM), a higher cofactor requirement, and a lower pH optimum was colocalized with the first form. Both turtle MD activities remain active over a range of temperatures, allowing for activity at the preferred body temperature of this species (28 to 37 degrees C compared to the 37 degrees C optimum in the rat). Based on limited comparative data of MD systems from several fish and birds, the turtle most closely resembles avian species. Like birds, turtles possess a mammalian-like type I activity and have colocalized MD forms in the liver. However, the second turtle MD form (MDH) is not comparable to the mammalian or avian MDII-like activity. Analysis of the deiodinase products from both turtle MDs by high-performance liquid chromatography confirmed that the putative turtle MDI produces T3 from T4 as expected. The MDH produces rT3 from T4 as does the mammalian type III form, but MDH has a wider tissue distribution (kidney, liver, pancreas, heart, ovary, and brain) and distinct enzyme kinetics. Moreover, MDH activity in the turtle kidney is 100-fold higher than in the liver, indicating that the kidney may play a critical role in the metabolism of thyroid hormones in the turtle; this high renal activity distinguishes the turtle from all other vertebrates studied.

Animals↗
PubMed1999

Testis-like steroidogenesis in the ovotestis of the European mole, Talpa europaea.

The female European mole (Talpa europaea) presents a vivid paradox in relation to our contemporary understanding of mammalian sexual differentiation. These animals are exceptional among female mammals in that they possess bilateral ovotestes. The ovotestis contains a morphologically normal ovarian component that develops during the spring breeding season and a histologically defined testicular region, the interstitial gland, which enlarges during autumn when the ovarian component decreases in size. In correlation with this unusual gonadal situation, the female mole displays a penile clitoris traversed by a urethral canal. Although the histology of the ovotestis is well documented and has recently been extended to an additional three species of the genus Talpa, there have been no clear indications of the physiological function, particularly androgen production, of the ovotestis in these female moles. This paper presents the first clear evidence of seasonal variation in plasma testosterone concentrations, which parallel the growth and regression of the "testicular" interstitial gland, in T. europaea. Plasma androstenedione did not show significant seasonal variation, but plasma testosterone (1.06 +/- 0.2 ng/ml) and gonadal testosterone concentration (1.57 +/- 0.65 microgram/mg protein) in females in autumn were significantly higher (p < 0.02) than plasma (0.4 +/- 0.2 ng/ml) and gonadal (0.24 +/- 0.21 microgram/mg) concentrations in pregnant or immediately postpartum females in spring. Our data also reveal selective metabolic production of testosterone from radiolabeled steroid precursors (progesterone and androstenedione) by these ovarian interstitial tissues and male testes; estradiol is produced by ovarian tissue but not interstitial gland or testis.

Androstenedione↗
PubMed1998

Immunochemical identification of thyrotropes and gonadotropes in the pars distalis and pars tuberalis of the toad (Bufo boreas) with reference to ontogenic changes.

Morphologically distinct secretory cells in the pituitary pars distalis and pars tuberalis of larval and adult toads (Bufo boreas) immunoreactive cells in the pars distalis. Thyrotropin immunoactivity appears in pars tuberalis and pars distalis before gonadotropin immunoreactivity during early development. Antisera which distinguish gonadotropes (stained with human and sea turtle LH beta) and thyrotropes (stained with human TSH beta) as separate cell types in the pars distalis of the adult toad immunoreact with the same single type of cell in the pars distalis of the tadpole up through metamorphosis, suggesting the existence of a single pluripotent, glycoprotein-producing precursor cell early in development. Gonadotropin antisera do not react with the pars tuberalis in tadpoles or adults.

Animals↗
PubMed1998

Identification and structural characterization of a novel member of the vitamin D binding protein family.

The apparent high degree of homology of a blood protein with a unique dual binding affinity for two distinct hormones, thyroxin (T4) and vitamin D, isolated from a turtle, Trachemys scripta (Family Emydidae) and mammalian vitamin D binding protein (DBP) prompted further interspecific comparison to better understand the structure of functional binding sites. Using polymerase-chain reaction (PCR) with primers derived from the putative nucleotide sequences encoding peptides from the degradation of the T. scripta protein, we cloned the cDNA. The mature turtle protein contains 466 amino acids, about eight residues more than in mammalian DBP. The nucleotide sequence of the coding region showed 63% nucleotide and 73% amino acid homology (approximately 53% identity) to mammalian DBP (human, rat, mouse, and rabbit). However, there was no significant homology to mammalian T4-binding globulin (TBG) or transthyretin (TTR). Comparisons with mammals help define further the requirements for the vitamin D and actin binding sites. Northern blots of RNA isolated from turtle tissue probed with the 5' portion of cDNA established expression of the transcript in liver, kidney, and brain (in order of abundance), in contrast to mammal sequences in which expression of DBP is largely confined to the liver.

Amino Acid Sequence↗
PubMed1998

Estradiol phase shifts circannual body mass rhythms of male ground squirrels.

Gonadectomized male golden-mantled ground squirrels (Spermophilus lateralis) were implanted with estradiol benzoate (EB)-filled or empty capsules. Body mass was monitored before, during, and for at least 1 yr after hormone treatment. EB treatment during the mass-gain phase of the annual cycle significantly decelerated increases in body mass; the period of the circannual rhythm (CAR) of body mass was 54 days longer in EB- than blank-treated squirrels. Hormone treatment during the mass-loss phase accelerated mass loss; although this effect only approached statistical significance, some phase markers of the CAR were significantly advanced in subsequent cycles. We conclude that, as in females, estradiol affects the waveform of the CAR of males differently at different phases of the circannual cycle. Sexual differentiation does not eliminate responsiveness of CARs of squirrels to estradiol; sex differences, if any, are subtle rather than absolute and, in this respect, differ from circadian rhythms.

Animals↗
PubMed1998

Androgens and masculinization of genitalia in the spotted hyaena (Crocuta crocuta). 1. Urogenital morphology and placental androgen production during fetal life.

According to common understanding of sexual differentiation, the formation and development of a penile clitoris in female spotted hyaenas requires the presence of naturally circulating androgens during fetal life. The purpose of the present study was to determine potential source(s) of such fetal androgens by investigating the timing of urogenital development and placental production of androgen during early and mid-gestation. Fetuses determined to be female by molecular techniques (lack of SRY gene) at days 33 and 48 of gestation had undifferentiated gonads, but the clitoris was already 'masculinized' and was generally similar to the phallus of a 50-day-old male fetus. Wolffian and Müllerian ducts terminated at the urogenital sinus in both sexes and a urethra was present along the entire length of the clitoris and penis. The adrenal gland was large and histologically differentiated at 33 days. Steroid gradients across the uterus (a drop in delta 4-androstenedione, with increases in oestrogen and androgen), and high androstenedione in ovarian veins indicated that ovarian androstenedione was metabolized and secreted as testosterone by the placenta throughout gestation. In vitro, whole or homogenized placentae at days 48 and 58 of gestation (110 days total) metabolized radiolabelled androstenedione into testosterone and oestradiol; the specific enzymatic activity of early placental tissues was higher than at later stages. A human placental homogenate had higher aromatase activity but did not produce testosterone unless aromatase was inhibited. Infusion of labelled androstenedione into the uterine arteries of hyaenas demonstrated the conversion of this substrate into testosterone and oestradiol and their secretion into the fetal circulation. Evidently, androgen is produced by the placenta and secreted into the fetal circulation from early in pregnancy when masculinization is first evident, before differentiation of the fetal ovary.

Androgens↗
PubMed1998

Androgens and masculinization of genitalia in the spotted hyaena (Crocuta crocuta). 2. Effects of prenatal anti-androgens.

Pregnant spotted hyaenas were treated with anti-androgens to interfere with the unusually masculine 'phallic' development that characterizes females of this species. The effects on genital morphology and plasma androgen concentrations of infants were studied during the first 6 months of life. Although there were consistent 'feminizing' effects of prenatal anti-androgen treatment on genital morphology in both sexes, such exposure did not produce males with extreme hypospadia, as it does in other species, nor did it produce females with a 'typical' mammalian clitoris and external vagina. 'Feminization' of males resulted in a penis with the morphological features of the hyaena clitoris, and 'feminization' of females exaggerated the sex differences that are typical of this species. The effects of treatment were present at birth and persisted for at least 6 months. Treatment of pregnant females with flutamide and finasteride also markedly reduced circulating concentrations of testosterone and dihydrotestosterone in maternal plasma during pregnancy. Plasma delta 4-androstenedione was reduced in the female, but not the male, infants of treated mothers, consistent with an epigenetic hypothesis previously advanced to explain hormonal 'masculinization' of females. The present 'feminizing' effects of prenatal anti-androgen treatment are consistent with contemporary understanding of sexual differentiation, which accounts for morphological variation between the sexes in terms of steroids. However, current theory does not account for the basic genital structure of females and the present data suggest that development of the male penis and scrotum, and the female clitoris and pseudoscrotum, in spotted hyaenas may involve both androgen-dependent and androgen-independent components.

5-alpha Reductase Inhibitors↗
PubMed1998

Androgens and masculinization of genitalia in the spotted hyaena (Crocuta crocuta). 3. Effects of juvenile gonadectomy.

Studies involving the administration of anti-androgens to spotted hyaenas during fetal development have raised questions concerning the precise contributions of steroids to phallic growth in these animals. If gonadal androgens promote postnatal penile growth in males, the following would be expected: (a) a period of accelerated growth accompanying achievement of puberty, and (b) a marked reduction in adult penile size and density of penile spines after gonadectomy. If a similar androgenic pubertal process stimulates clitoral growth in these highly 'masculinized' hyaenas, parallel observations in females would be expected; however, the role of oestrogens in accounting for female-typical clitoral development would also have to be considered. The results of the present study suggest a limited role, if any for androgenic stimulation of phallic growth. That is, penile growth was greater during the 10 month period preceding puberty, than during an 18-month period that included the traditional increase in pubertal androgens. In addition, pre-pubertal castration had minimal effects on penile length, diameter, or the presence of penile spines. In females, most clitoral growth also occurred before puberty, although pre-pubertal ovariectomy produced significant reductions in clitoral diameter and the elasticity of the urogenital meatus. These feminine characteristics which normally distinguish the female from the male phallus in this species, were partially restored by a brief period of oestrogen administration. Both sexes displayed erections many years after pre-pubertal castration. The results of the present study suggest that postnatal phallic growth is largely independent of gonadal steroids, with oestrogenic facilitation of female-typical clitoral characteristics in spotted hyaenas.

Androgens↗
PubMed1998

[Luteal and extraluteal receptors for hCG and LH].

The hCG/LH receptor belongs to the G-protein coupled receptor family. The gene for the receptor has been localised to chromosome 2p21. In addition to corpus luteum and testis as the classical target tissues for hCG and LH, hCG/LH receptors have been described in a variety of non-gonadal human tissues (e.g. endometrium, myometrium, fallopian tube, placenta, amnion, chorion, prostate, CNS, adrenal gland). Besides its modulation of endocrine functions, the hCG/LH receptor does probably transmit growth-factor like activities of hCG and LH in many of these tissues. Moreover, activating as well as inactivating mutations of the hCG/LH receptor gene have been described. These mutations are localised mainly within the transmembrane region of the receptor gene (exon 11) and are responsible for characteristic diseases such as familiar, male-limited precocious puberty as well as hypogonadism of both sexes. This review deals with the molecular biology of the hCG/LH receptor, its distribution within the human body, its functions as well as with the relevance of mutations. Finally, the therapeutic use of hCG in the treatment of AIDS-related Kaposis' sarcoma is discussed.

Chorionic Gonadotropin↗
PubMed1997

Seasonal changes in gonadal activity and the effects of stress on reproductive hormones in the common snapping turtle, Chelydra serpentina.

The seasonal gonadal cycle (including gonadal histology, sex steroids, and gonadotropins) was studied in freshly captured common snapping turtles, Chelydra serpentina, from Wisconsin, and the effects of capture stress were evaluated. The ovarian and testicular cycles are shorter than those reported in other freshwater turtles; the cycles commence in mid-May and terminate in early September, immediately after the completion of gonadal growth and maturation. In the female, testosterone (T), 17beta-estradiol (E2), and progesterone (Pro) were highly correlated with follicular growth and vitellogenesis. Ovulation in captivity and under natural conditions occurred after mid-May. In captivity, ovulation was a rapid process (24-48 hr); as the follicles descended into the uterine horns there was a significant increase in E2 and Pro and eggs were retained in the uterine horns for about 2 weeks before oviposition. In the male, T was significantly correlated with testicular growth and spermiation. Follicle-stimulating hormone (FSH) reached significantly higher levels (P < 0.01) in males (8.99 +/- 0.38 ng/ml) than in females (2.66 +/- 0.22 ng/ml), but luteinizing hormone was undetectable in both sexes. FSH was not correlated with the steroids in either sex. Sex steroids and FSH began to rise before spermiation and vitellogenesis and remained elevated until completion of gonadal growth and maturation. Leydig cells, the main source of plasma androgen in this species, became active shortly after emergence from hibernation and remained steroidogenically active for the rest of the cycle. Sertoli cells became active only after spermatogenesis was under way but also stayed active for the rest of the summer. Courtship and mating behaviors were observed in spring, summer, and fall. The snapping turtle is strictly aquatic with no basking behavior and limited behavioral thermoregulation so there is little daily fluctuation in body temperature. Environmental correlates indicate that the snapping turtle is temperature dependent: recrudesence occurs with a slight increase in water temperature during spring and early summer, while a dramatic drop in gonadal activity accompanies a slight decrease in temperature in fall. Changes in temperature may underlie changes in gonadal activity in the face of relatively stable FSH. Male turtles subjected to captivity and periodic blood sampling show a significant decline in T. The hormonal levels continued to decline whether the turtles are exposed to optimum or extreme temperatures. However, there is more rapid decline in T values in animals with regressed testes (June) than in those with well-developed testes (July). Male and female turtles kept in captivity at different phases of the cycle exhibit different patterns and degrees of response to stress, possibly related to the hormonal levels and the condition of the gonads.

Animals↗