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Biomedical subjects

Taneli Raivio

Publications and source records attributed to Taneli Raivio.

At least 19 recordsLinked to original sources
PubMed2007

Treatment of gonadotropin-deficient boys with recombinant human FSH: long-term observation and outcome.

BACKGROUND: Boys with prepubertal onset of hypogonadotropic hypogonadism (HH) are at a risk of poor testis growth and impaired spermatogenesis. One potential cause for this is deficient proliferation of immature Sertoli cells before and during puberty due to the absence of FSH. OBJECTIVE: To evaluate the effects of recombinant human FSH (r-hFSH) and human chorionicgonadotropin (hCG) on testicular function and pubertal development in boys with prepubertal onset of HH. DESIGN: Retrospective clinical study. SETTING: Two university central hospitals, pediatric referral endocrinology outpatient clinics. PATIENTS: Fourteen boys (aged, 9.9-17.7 years) with prepubertal (testicular volume (TV) <3 ml) onset of HH (idiopathic HH, n=2; Kallman syndrome, n=2; idiopathic panhypopituitarism, n=4; organic panhypopituitarism, n=6). INTERVENTION: Treatment with r-hFSH alone (2 mo-2.8 years) prior to induction of puberty with the combination of FSH and hCG. MAIN OUTCOME MEASURES: Progression of puberty, change in serum inhibin B, spermatogenesis. RESULTS: r-hFSH alone increased testicular volume twofold, from 0.9+/-0.6 ml (mean+/-s.d.) to 1.8 +/- 1.1 ml (P<0.005), and serum inhibin B threefold, from 27+/-14 to 80+/-57 pg/ml (P<0.01). Three boys with an apparent absence of postnatal hypothalamic-pituitary-testicular axis activation displayed attenuated inhibin B responses to long-term (>or=1 year) r-hFSH (P<0.01). Further significant increase in both TVand inhibin B occurred with induction of puberty with FSH and hCG (P<0.001). Seven boys provided semen samples: one had azoospermia, and others displayed a maximal sperm count range from 2.9 to 92 million/ml (median 8.5 million/ml). CONCLUSIONS: (i) r-hFSH induces prepubertal testis growth and increases circulating inhibin B levels, findings suggesting proliferation of immature Sertoli cells. (ii) Puberty was successfully induced with hCG and r-hFSH following r-hFSH priming. (iii) Inhibin B appears useful for monitoring spermatogenetic activity in boys treated with hCG. (iv) Despite the extremely small initial testis volume, six out of seven patients (86%) primed with r-hFSH displayed sperm in the ejaculate suggesting beneficial effect of r-hFSH priming on testicular function later in life.

Adolescent↗
PubMed2006

The effects of short-term oral phytoestrogen supplementation on the hypothalamic-pituitary-testicular axis in prostate cancer patients.

BACKGROUND: Here we evaluate the effects of oral phytoestrogen supplementation on hypothalamic-pituitary-testicular (HPT) axis in CaP patients. METHODS: We recruited 40 men about to undergo radical prostatectomy for CaP to receive either 240 mg of clover phytoestrogens or placebo daily for 2 weeks. Serum hormone levels were measured before and after treatment. In addition, recombinant cell bioassay was used to measure serum androgen bioactivity (ABA). RESULTS: Phytoestrogen treatment increased serum LH from mean of 3.4-5.2 IU, P = 0.03. Concomitantly, non-significant trend towards decline in serum T, cfT and ABA values was noted. However, mean serum LH/T ratio was upregulated from 0.20 to 0.48 IU/nM, P = 0.004, suggesting compensated hypogonadism. During the course of treatment, serum concentration of equol correlated strongly with the concomitant decrease in ABA (r = -0.586, P = 0.022). CONCLUSIONS: Phytoestrogen treatment interferes with HPT axis in CaP patients by inducing testicular resistance to LH and compensated hypogonadism.

Administration, Oral↗
PubMed2006

Are adolescent boys with Klinefelter syndrome androgen deficient? A longitudinal study of Finnish 47,XXY boys.

Testosterone (T)-substitution therapy is widely used in adult patients with Klinefelter syndrome (KS) to prevent symptoms and sequels of androgen deficiency, but it is currently unknown if adolescent boys with KS benefit from early T therapy. To evaluate the optimal age to start T substitution, we searched for signs of androgen deficiency in pubertal boys with KS. 14 nonmosaic 47,XXY boys, aged 10-13.9 y, were followed up for 4-37 mo with staging of puberty and frequent reproductive hormone measurements. Furthermore, indices reflecting androgen action (serum SHBG, leptin, and prostate-specific antigen (PSA) levels) were studied. Both onset and progression of puberty according to Tanner stages were normal in boys with KS. Consistently, serum T concentrations increased as expected and remained normal throughout follow-up. Changes in the indices of androgen action (decreases in serum SHBG and leptin, and increase in serum PSA concentrations) occurred normally, except that average leptin levels were higher in the boys with KS (KS boys 11.8 +/- 7.0 microg/L; controls 7.6 +/- 4.7 microg/L; p = 0.033). Despite normal T concentrations, the KS boys displayed from the age of 13 y elevated serum FSH and LH levels, and exaggerated gonadotropin responses to gonadotropin-releasing hormone. These data do not demonstrate an unequivocal androgen deficiency in adolescent boys with KS that would necessitate androgen supplementation therapy during early puberty.

Adolescent↗
PubMed2006

Fecal calprotectin remains high during glucocorticoid therapy in children with inflammatory bowel disease.

OBJECTIVE: Fecal calprotectin is a promising marker for the assessment of gastrointestinal inflammation. Fecal calprotectin levels were followed-up in children with inflammatory bowel disease (IBD) who were introduced to glucocorticoid therapy. The aim of this study was to assess whether the changes in fecal calprotectin levels reflect therapeutic responses. MATERIAL AND METHODS: Fecal calprotectin was measured by enzyme immunoassay in 57 children (mean age 9.8 years, range 0.9-18 years) who underwent colonoscopies (IBD n=31, non-IBD disease n=13, normal n=13) and followed-up in 15 children (mean age 13 years, range 3.6-18 years) who were introduced to glucocorticoid therapy because of active IBD at 0, 2, and 4 weeks and at 4-week intervals until one month after discontinuation of the therapy. RESULTS: Fecal calprotectin was <100 microg/g in 70% of the children with normal findings on colonoscopy or a non-IBD disease. Fecal calprotectin was >100 microg/g in all but one child with active IBD and in 13/15 of those children who were introduced to glucocorticoids by the clinicians. Fecal calprotectin values decreased within 4 weeks in line with clinical improvement in 7 children and normalized in 4/15 children during the follow-up. Fecal calprotectin increased in 5/8 of the non-steroid-dependent children after discontinuation of glucocorticoids. CONCLUSIONS: Fecal calprotectin is a sensitive marker for chronic colitis. In active disease treated with glucocorticoids, fecal calprotectin levels declined in line with the clinical improvement but seldom fell within the normal range, which suggests ongoing inflammation in a clinically silent disease. The measurement of fecal calprotectin may provide new tools for the assessment of the level of gut inflammation in children with chronic colitis in the follow-up of clinical responses.

Adolescent↗
PubMed2006

Genetic features of the X chromosome affect pubertal development and testicular degeneration in adolescent boys with Klinefelter syndrome.

OBJECTIVE: To investigate how genetic features of the X chromosome influence growth, pubertal development and testicular degeneration in adolescent boys with Klinefelter syndrome (KS). Previous studies have suggested that genetic features of the X chromosome may contribute to the wide phenotypic variation in KS. DESIGN: A prospective clinical study. PATIENTS: Fourteen nonmosaic 47,XXY boys, aged 10-13.9 years. MEASUREMENTS: The relationship of genetic features of the X chromosome, including parental origin of X chromosomes, the CAG repeat length of the androgen receptor (AR) gene, and X inactivation with progression of pubertal development, growth and testicular function in KS boys. RESULTS: Paternal (47,XmXpY, n = 3) as compared to maternal (47,XmXmY, n = 11) origin of the supernumerary X chromosome was associated with a later onset of puberty. In 47,XmXpY patients, serum LH concentrations increased above 1.0 IU/l at 12.5 +/- 0.6 years (mean +/- SD), Tanner stage P2 occurred at 12.5 +/- 0.7 years, and pubertal acceleration of growth was noted at 13.9 +/- 1.4 years and peak velocity at 14.5 +/- 0.8 years. All of these occurred 1.3-1.9 years later than in 47,XmXmY patients (P = 0.01-0.09). In 47,XmXmY subjects, CAG repeat length (range 17-26) correlated with age at which serum LH level first exceeded 1.0 IU/l (rs = 0.63, P = 0.06, n = 10) and testosterone 1.0 nmol/l (28.8 ng/dl) (rs = 0.78, P = 0.02, n = 10). CONCLUSIONS: Paternal origin of the supernumerary X chromosome is associated with later onset of puberty and longer CAG repeats of the AR with later pubertal reactivation of the pituitary-testicular axis in KS boys. Identifying genetic factors that affect the phenotype may lead to a better understanding of the pathogenesis of KS.

Adolescent↗
PubMed2005

Identification of glucocorticoid-response genes in children with acute lymphoblastic leukemia.

The ability of glucocorticoids (GCs) to kill lymphoid cells led to their inclusion in essentially all chemotherapy protocols for lymphoid malignancies, particularly childhood acute lymphoblastic leukemia (ALL). GCs mediate apoptosis via their cognate receptor and subsequent alterations in gene expression. Previous investigations, including expression profiling studies with subgenome microarrays in model systems, have led to a number of attractive, but conflicting, hypotheses that have never been tested in a clinical setting. Here, we present a comparative whole-genome expression profiling approach using lymphoblasts (purified at 3 time points) from 13 GC-sensitive children undergoing therapy for ALL. For comparisons, expression profiles were generated from an adult patient with ALL, peripheral blood lymphocytes from GC-exposed healthy donors, GC-sensitive and -resistant ALL cell lines, and mouse thymocytes treated with GCs in vivo and in vitro. This generated an essentially complete list of GC-regulated candidate genes in clinical settings and experimental systems, allowing immediate analysis of any gene for its potential significance to GC-induced apoptosis. Our analysis argued against most of the model-based hypotheses and instead identified a small number of novel candidate genes, including PFKFB2, a key regulator of glucose metabolism; ZBTB16, a putative transcription factor; and SNF1LK, a protein kinase implicated in cell-cycle regulation.

Adolescent↗
PubMed2005

Circulating antiandrogenic activity in children with congenital adrenal hyperplasia during peroral flutamide treatment.

CONTEXT: The degree of androgen receptor blockade achieved with peroral flutamide is unknown. OBJECTIVE: The aim of this study was to examine the contribution of flutamide to circulating antiandrogenic activity in children with congenital adrenal hyperplasia using a recombinant cell bioassay. DESIGN: We describe an open-label, prospective clinical study. SETTING: The study was conducted at the Hospital for Children and Adolescents, University of Helsinki, or the Turku University Hospital, Finland. PARTICIPANTS: Seven children, age 7.2-10.5 yr, were included. INTERVENTION: As an experimental approach to improve control of height velocity and the rate of bone maturation, the patients received letrozole (2.5 mg/d) and flutamide (10 mg/kg.d) and were followed up at 3-month intervals for 3-12 months. Before employing the bioassay, two pools of sera (obtained before and during flutamide treatment) were supplemented with increasing amounts of testosterone, and all sera (n = 27) of individual patients were supplemented with a constant amount of exogenous testosterone. MAIN OUTCOME MEASURE: The main outcome measure was circulating antiandrogenic activity. RESULTS: Flutamide and/or its metabolites shifted the dose-response curve of testosterone, in that only the highest testosterone concentration, corresponding to 1803 ng/dl (62.5 nm) in human serum, was measurable by the bioassay. In individual sera supplemented with testosterone, flutamide treatment suppressed androgen bioactivity from 378 +/- 20 ng/dl (13.1 +/- 0.7 nm) (mean +/- sem) (pretreatment) to 110 +/- 20 ng/dl (3.8 +/- 0.7 nm) (3 months), 83.7 +/- 12 ng/dl (2.9 +/- 0.4 nm) (6 months), 46.2 +/- 6 ng/dl (1.6 +/- 0.2 nm) (9 months), and 57.7 +/- 9 ng/dl (2.0 +/- 0.3 nm) (12 months) testosterone equivalents (P < 0.01). CONCLUSIONS: A dose of flutamide less than 10 mg/kg.d appears sufficient to inhibit AR in children. The recombinant cell bioassay employed herein offers a novel means to monitor the treatment of patients receiving antiandrogens.

Administration, Oral↗
PubMed2005

Late follicular phase administration of mifepristone suppresses circulating leptin and FSH - mechanism(s) of action in emergency contraception?

OBJECTIVE: Low dose mifepristone (RU486) is highly effective in emergency post-coital contraception (EC), although the mechanism(s) of action remains unclear. We studied the endocrine actions of 10 mg mifepristone administered orally as a single dose to eight healthy volunteers (aged 20-45 years) during the late follicular phase. METHODS: Serum levels of LH, FSH, oestradiol, progesterone, leptin, mifepristone, cortisol, and gluco-corticoid bioactivity (GBA) were measured before and 1, 2, 4 and 8 h after ingestion of mifepristone on cycle day 10 or 11 (study day 1), and follow-up was continued for 10 days. Ovarian ultrasonography was performed on study days 1 and 7. Similar measurements were carried out during a control cycle. RESULTS: Mifepristone postponed ovulation, as evidenced by a 3.4+/-1.1 day (means+/-s.d.) delay (P < 0.005) in the LH surge and 3.6+/-4.0 day prolongation of the treatment cycle (P = 0.08). During the mifepristone cycle, an LH surge was displayed by five subjects when serum mifepristone levels had declined to 9.5+/-7.1 nmol/l. During the day of mifepristone administration, circulating GBA (P < 0.001) and leptin (P < 0.001) levels declined. On the day after mifepristone administration, mean serum FSH and leptin levels were lower than pretreatment values (3.8+/-1.8 IU/l vs 5.2+/-1.1 IU/l, n = 7, P < 0.05; 28.9+/-6.7 microg/l vs 33.2+/-9.0 microg/l, n = 7, P < 0.05 respectively), and the corresponding difference in the mean serum oestradiol concentration was borderline (452+/-252 pmol/l vs 647+/-406 pmol/l, n = 7, P = 0.056). In contrast to the control cycle, individual leptin levels declined during the follow-up after ingestion of mifepristone (n = 8, P < 0.01). CONCLUSIONS: These data showed that the commonly employed dose of mifepristone for EC delays ovulation and prolongs the menstrual cycle, when given during the late follicular phase. The mechanism of action of mifepristone may include a reduction of FSH secretion via a decrease in circulating leptin.

Adult↗
PubMed2004

Serum androgen bioactivity in adolescence: a longitudinal study of boys with constitutional delay of puberty.

We have examined the relationship between serum androgen bioactivity, as measured with a recombinant cell bioassay, and progression of puberty in 14 boys with constitutional delay of puberty. Six boys were followed up without treatment (control group), and eight boys received low-dose (1 mg/kg) testosterone enanthate im for 0-6 months together with an aromatase inhibitor, letrozole, 2.5 mg orally once a day for 0-12 months (treatment group). In the control group, serum androgen bioactivity increased during the course of puberty (P < 0.001). During 0-12 months of the study, the boys in the treatment group had higher androgen bioactivity levels (P < 0.05) and faster rate of pubic hair growth than the control boys (P < 0.05). Overall, the average serum androgen bioactivity during 12 months of follow-up correlated strongly with the concomitant changes in Tanner genital (r(S) = 0.89; n = 13; P < 0.005) and pubic hair stages (r(S) = 0.79; n = 13; P < 0.01). In conclusion, our results suggest that circulating androgen bioactivity mediates the tempo of pubertal maturation and that the combination of testosterone and letrozole given to boys with constitutional delay of puberty accelerates puberty.

Adolescent↗
PubMed2004

Klinefelter syndrome in adolescence: onset of puberty is associated with accelerated germ cell depletion.

The process of germ cell depletion in patients with Klinefelter syndrome (KS) is incompletely characterized. In the current work, we evaluated the presence of germ cells in adolescent boys with KS for possible future use in assisted reproduction techniques. Fourteen nonmosaic 47,XXY boys (aged 10-14 yr) were enrolled. Every fourth month their puberty was staged, and serum was obtained for hormone analyses. Each boy underwent a single testicular biopsy. Biopsy specimens of seven peripubertal boys (testicular volume < 2.0 ml) had spermatogonia of adult type, whereas older boys with larger testes (> 2.0 ml) exhibited no germ cells. No meiotic germ cells were detectable in any of these subjects. Depletion of germ cells was associated with an increase in testicular volume but was not immediately reflected in levels of serum gonadotropin, inhibin B, or anti-Müllerian hormone. In contrast, hypergonadotropism and suppression of serum inhibin B and anti-Müllerian hormone developed later, during midpuberty, after an unequivocal increase in serum testosterone (>2.5 nmol/liter) levels and degeneration of Sertoli cells. In conclusion, these prepubertal and early pubertal boys with KS had diploid germ cells that vanished in early puberty when testicular volume increased, whereas serum gonadotropin and inhibin B levels displayed pathological changes later during midpuberty.

Adolescent↗
PubMed2004

Circulating glucocorticoid bioactivity in the preterm newborn after antenatal betamethasone treatment.

Antenatal glucocorticoid treatment of mothers at risk of premature delivery is highly cost-effective in reducing neonatal mortality and morbidity. However, there is only limited information on the actual glucocorticoid bioactivity (GBA) reaching the fetus. By employing a recently developed recombinant cell bioassay, we studied circulating GBA in preterm newborns exposed to the standard antenatal betamethasone regimen (12 mg betamethasone twice, 24-h interval, for the mother; repeated in 7-10 d if required). Plasma GBA and cortisol concentrations were measured in cord blood of 71 infants (mean gestational age, 28.9 wk; range, 24.6-32 wk; mean birth weight, 1208 g; range, 480-2010 g). The median time between the last administered betamethasone dose and birth was 2.0 d. Cord GBA ranged from less than 15.6 to 170 nmol/liter cortisol equivalents. The level was highly dependent on the time between the last betamethasone dose and birth, i.e. infants born shortly (<12 h) after the last steroid dose displayed on average 4-fold higher GBA than that in the reference group (infants with >7 d since the last betamethasone dose before birth or without treatment; 74 vs. 21 nmol/liter cortisol equivalents; P < 0.0001). By contrast, if more than 72 h had elapsed between the last steroid dose and birth, circulating GBA was strongly dependent on cord cortisol (r = 0.85; P < 0.0001; n = 30). In multiple regression analysis adjusted for cord cortisol concentration and the time since the last steroid dose, increased umbilical artery resistance, a sign of severe fetal distress, was associated with lower cord GBA (P = 0.01). In conclusion, antenatal exposure of preterm fetuses to betamethasone causes a sizeable, but brief, peak of supraphysiological GBA, and approximately 3 d after the last betamethasone dose, circulating GBA derives from cord cortisol concentration.

Betamethasone↗
PubMed2003

Reduced circulating androgen bioactivity in patients with prostate cancer.

BACKGROUND: Previous studies on immunoreactive androgen levels in serum have revealed equivocal associations with the risk of prostate cancer (CaP). The aim of this study was to compare serum biological androgen activity between men with newly diagnosed CaP and age-matched men with benign prostatic hyperplasia (BPH). METHODS: Caucasian men with newly diagnosed, untreated CaP (n = 101) and age-matched patients with BPH (n = 103) were investigated. Serum androgen bioactivity (ABA) levels were measured using a recently developed recombinant cell bioassay. RESULTS: In comparison to men with BPH, CaP patients with Gleason score >or=8 (n = 16) had lower serum ABA (P < 0.05), and patients with Gleason score or=8 (P = 0.07) displayed suppressed ABA levels in relation to serum testosterone. As the entire group, men with CaP (n = 101) had significantly lower serum ABA than age-matched men with BPH (n = 103): median 3.0 nM (range, 0.8-6.4 nM) versus 3.2 nM (range, 0.8-7.9 nM) testosterone equivalents, respectively (P < 0.005). By contrast, serum immunoreactive testosterone and SHBG concentrations and free androgen indices did not differ significantly between the two groups. CONCLUSIONS: Patients with CaP have lower serum ABA than controls with BPH, and men with low or high Gleason score display suppressed circulating ABA-to-testosterone ratio. These features may reflect interaction between variables such as the degree of tumor differentiation and tumor volume with androgen metabolism.

Aged↗
PubMed2003

Termination of pregnancy with mifepristone and prostaglandin suppresses transiently circulating glucocorticoid bioactivity.

Mifepristone is a potent antiglucocorticoid, the administration of which results in a dose-dependent activation of the hypothalamic-pituitary-adrenal axis. However, the net effect of this compound on circulating glucocorticoid activity is not known. We have used a recombinant cell bioassay to study glucocorticoid bioactivity (GBA), measured directly from serum, in 18 women undergoing medical termination of an early pregnancy with 200 mg mifepristone, followed by 0.8 mg misoprostol, a prostaglandin. Increased serum mifepristone was accompanied by an increase in serum cortisol that was insufficient to maintain circulating GBA within the normal (pre-mifepristone) range (34.7-93.8 nM cortisol equivalents); after approximately 43, 46, and 68 h of mifepristone ingestion, the mean serum GBA levels were much lower than the mean pre-mifepristone level (P < 0.0001). At the corresponding times, 16, 13, and 12 women displayed subnormal serum GBA levels (ranges, <15.6-23, <15.6-25.6, and <15.6-32.5 nM cortisol equivalents, respectively). Altogether 11 subjects displayed subnormal serum GBA (range, <15.6-32.5 nM cortisol equivalents) continuously in the presence of high concentrations of mifepristone. Two weeks after mifepristone administration, circulating GBA had returned to normal levels in all subjects. We conclude that 200 mg mifepristone elicits a significant suppression of serum GBA, to one third of the pretreatment value, despite the compensatory increase in the serum cortisol concentration.

Abortifacient Agents, Nonsteroidal↗
PubMed2003

Serum androgen bioactivity in cryptorchid and noncryptorchid boys during the postnatal reproductive hormone surge.

The first postnatal months of life in boys are characterized by activation of the hypothalamic-pituitary-testicular axis that results in the well depicted surge of reproductive hormones. Serum testosterone levels at that time are high, but infants do not display signs of virilization, and subsequently there is only indirect evidence that circulating androgens during the surge are biologically active. We used a recombinant cell bioassay to determine serum androgen bioactivity in 80 3-month-old boys born after full-term pregnancies (37-42 wk) in whom localization of the testes was determined by palpation after birth and at a mean age of 3 months. At that age, serum androgen bioactivity ranged from less than 0.8 to 1.9 nM testosterone equivalents and correlated with serum testosterone concentration (r = 0.71; P < 0.0001; n = 34), free androgen index (r = 0.80; P < 0.0001; n = 34), age (r = -0.29; P < 0.01; n = 80), and localization of the testes (r = -0.24; P < 0.05; n = 80). Moreover, all boys in this study with detectable androgen bioactivity (n = 26) had testes located in scrotal or high scrotal position (n = 64), whereas all boys (n = 16) with at least 1 suprascrotal, inguinal, or nonpalpable testis had nonmeasurable androgen bioactivity in serum (P < 0.01). We conclude that 3-month-old boys are exposed to biological effects of androgens during the postnatal activation of the hypothalamic-pituitary-testicular axis, and that this exposure may be reduced in boys with at least 1 testis located superior to the scrotum.

Androgens↗
PubMed2002

Inhibins in childhood and puberty.

Inhibin is a heterodimeric glycoprotein that consists of an alpha-subunit linked to either a betaA subunit (inhibin A) or to a betaB subunit (inhibin B) and it exists in at least six different isoforms. These isoforms can not be measured separately by immunoassays. In boys, serum inhibin B levels change in concert with the increase in gonadotrophins. Associated with the postnatal activation of gonadotrophin secretion, the early inhibin B secretion is sustained until the age of 18-24 months; thereafter serum concentrations subside. In boys, between Tanner stages G1 and G2, serum inhibin B concentration again increases, but then plateaus. Inhibin A levels in human males are below the detection limit, but in girls, during the postnatal activation of gonadotrophin secretion, both serum inhibin A and inhibin B concentrations are measurable. Serum inhibin B levels correlate positively with age several years before the clinical onset of puberty, suggesting increasing follicular activity in late prepuberty. During female puberty, the inhibin B level increases from Tanner stage B1 through stage B3, suggesting high follicular activity before the development of ovulatory menstrual cycles, but serum inhibin A levels become measurable later in puberty, in agreement with the idea that inhibin A is mainly produced by the corpus luteum.

Adolescent↗
PubMed2002

Activation of the bone morphogenetic protein signaling pathway induces inhibin beta(B)-subunit mRNA and secreted inhibin B levels in cultured human granulosa-luteal cells.

During the human menstrual cycle the circulating levels of inhibin B, a dimer of inhibin alpha- and beta(B)-subunits, fluctuate in a fashion distinct from that of inhibin A, the alpha-beta(A)-subunit dimer. This suggests that human inhibin subunits are each regulated in a distinct manner in human ovarian granulosa cells by endocrine and local factors. We have previously shown using cultures of human granulosa-luteal (hGL) cells that gonadotropins stimulate the steady state mRNA levels of inhibin alpha- and beta(A)-subunits, but not those of the beta(B)-subunit, which, on the other hand, are up-regulated by, for instance, activin and TGF beta. We recently identified the TGF beta gene family member bone morphogenetic protein-3 (BMP-3) as a granulosa cell-derived growth factor, but whether BMP-3 or other structurally related BMPs regulate human granulosa cell inhibin production is not known. We show here that hGL cells express mRNAs for distinct serine/threonine kinase receptors (BMP-RIA and BMP-RII) and Smad signaling proteins (Smad1, Smad4, and Smad5) involved in the mediation of cellular effects of BMPs. Subsequently, we determined in hGL cell cultures the effects of distinct members of the BMP family previously found to be expressed in mammalian ovaries. Recombinant BMP-2 induces potently in a time- and concentration-dependent manner the expression of the inhibin beta(B)-subunit mRNAs in hGL cells without affecting the levels of alpha- or beta(A)-subunit mRNAs. BMP-6 has a similar, but weaker, effect than BMP-2, whereas BMP-3 and its close homolog, BMP-3b (also known as growth differentiation factor-10) had no effect on inhibin subunit mRNA expression. hCG treatment of hGL cells was previously shown to abolish the stimulatory effect of activin on beta(B)-subunit mRNA levels, and here hCG is also shown to suppress the effect of BMP-2. Furthermore, BMP-2 stimulates hGL cell secreted dimeric inhibin B levels in a concentration-dependent manner. Depending on the experiment, maximal increases in inhibin B levels of 6- to 28-fold above basal levels were detected during a 72-h culture period. We conclude that activation of the BMP-signaling pathway in hGL cells stimulates inhibin beta(B)-subunit mRNA levels and leads at the protein level to a dramatic stimulation of secreted inhibin B dimers. Our results are consistent with the suggestion that in addition to the distinct activin- and TGF beta-activated signaling pathways, the BMP-activated pathway is likely to be implicated in the complex regulation of inhibins in the human ovary.

Bone Morphogenetic Protein 2↗