scholarly journals Recombinant Human FSH Treatment Outcomes in Five Boys With Severe Congenital Hypogonadotropic Hypogonadism

2018 ◽  
Vol 2 (12) ◽  
pp. 1345-1356 ◽  
Author(s):  
Ella Kohva ◽  
Hanna Huopio ◽  
Matti Hero ◽  
Päivi J Miettinen ◽  
Kirsi Vaaralahti ◽  
...  
Keyword(s):  
Sperm Count ◽  
Hypogonadotropic Hypogonadism ◽  
Inhibin B ◽  
Testis Size ◽  
Early Puberty ◽  
Count Range ◽  
Preservation Of Fertility ◽  
Prepubertal Boys ◽  
Small Testis ◽  
Recombinant Human Fsh

Abstract Context Recombinant human FSH (r-hFSH), given to prepubertal boys with hypogonadotropic hypogonadism (HH), may induce Sertoli cell proliferation and thereby increase sperm-producing capacity later in life. Objective To evaluate the effects of r-hFSH, human chorionic gonadotropin (hCG), and testosterone (T) in such patients. Design and Setting Retrospective review in three tertiary centers in Finland between 2006 and 2016. Patients Five boys: ANOS1 mutation in two, homozygous PROKR2 mutation in one, FGFR1 mutation in one, and homozygous GNRHR mutation in one. Prepubertal testicular volume (TV) varied between 0.3 and 2.3 mL; three boys had micropenis, three had undergone orchidopexy. Interventions Two boys received r-hFSH (6 to 7 months) followed by r-hFSH plus hCG (33 to 34 months); one received T (6 months), then r-hFSH plus T (29 months) followed by hCG (25 months); two received T (3 months) followed by r-hFSH (7 months) or r-hFSH plus T (8 months). Main Outcome Measures TV, inhibin B, anti-Müllerian hormone, T, puberty, sperm count. Results r-hFSH doubled TV (from a mean ± SD of 0.9 ± 0.9 mL to 1.9 ± 1.7 mL; P < 0.05) and increased serum inhibin B (from 15 ± 5 ng/L to 85 ± 40 ng/L; P < 0.05). hCG further increased TV (from 2.1 ± 2.3 mL to 8.6 ± 1.7 mL). Two boys with initially extremely small testis size (0.3 mL) developed sperm (maximal sperm count range, 2.8 to 13.8 million/mL), which was cryopreserved. Conclusions Spermatogenesis can be induced with gonadotropins even in boys with HH who have extremely small testes, and despite low-dose T treatment given in early puberty. Induction of puberty with gonadotropins allows preservation of fertility.

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

2007 ◽  
Vol 156 (1) ◽  
pp. 105-111 ◽  
Author(s):  
Taneli Raivio ◽  
Anne M Wikström ◽  
Leo Dunkel
Keyword(s):  
Sertoli Cells ◽  
Sperm Count ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Inhibin B ◽  
Testicular Volume ◽  
Testicular Function ◽  
Retrospective Clinical Study ◽  
Recombinant Human Fsh

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 (≥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.

scholarly journals Signaling between the pituitary gland and the testes: inverse relationship between serum FSH and inhibin B concentrations in boys in early puberty

2000 ◽  
pp. 150-156 ◽  
Author(s):  
T Raivio ◽  
S Saukkonen ◽  
J Jaaskelainen ◽  
J Komulainen ◽  
L Dunkel
Keyword(s):  
Tanner Stage ◽  
Inhibin B ◽  
Human Testis ◽  
Early Puberty ◽  
Assay Sensitivity ◽  
Reciprocal Regulation ◽  
Prepubertal Boys ◽  
The Difference ◽  
Age Range ◽  
Estradiol Levels

OBJECTIVES: To study the relationship between serum inhibin B and sex steroid concentrations and pituitary FSH responsiveness to GnRH in boys in early puberty, and to examine serum inhibin B levels in prepubertal boys with different timing of the onset of gonadotropin deficiency (GD). DESIGN: Twenty-five boys with constitutional delay of puberty (CDP; 20 in Tanner stage G2 and 5 in G3; age range, 13. 5-16.8 years) and eight prepubertal boys (G1P1) with GD (age range, 10.0-13.2 years) were clinically examined, and serum inhibin B, testosterone and estradiol concentrations were measured from sera obtained immediately before the administration of GnRH (Relefact; 3.5 microgram/kg, maximum 100 microgram i.v.). Thereafter, FSH levels were measured at 30min intervals up to 90min. RESULTS: In the boys with CDP, basal inhibin B and FSH levels did not correlate. However, inhibin B and GnRH-stimulated FSH concentrations (r(S)= -0.43 to -0.45, n=25, P<0.05) and the difference between basal and peak serum FSH levels were inversely related (r(S)= -0.63, n=25, P<0.005). This relationship remained significant in boys at stage G2 (r(S)= -0.66, n=20, P<0.005). Basal testosterone concentrations and GnRH-induced FSH levels did not correlate. Estradiol levels were too low (64% of the boys had estradiol levels below the assay sensitivity) to allow correlation analysis. The boys with GD had low inhibin B concentrations (range, <15.6-53pg/ml); the lowest levels were observed in boys with presumably congenital onset of the disease. Serum inhibin B levels and testis volumes correlated positively (r(S)=0.70, n=8, P=0.07). CONCLUSIONS: These results suggest that, in boys, the reciprocal regulation between inhibin B and FSH is in operation before mid-puberty. Moreover, autonomous inhibin B secretion by the prepubertal human testis is likely to reflect the number of Sertoli cells.

scholarly journals Early postnatal treatment of hypogonadotropic hypogonadism with recombinant human FSH and LH

2002 ◽  
pp. 75-79 ◽  
Author(s):  
KM Main ◽  
IM Schmidt ◽  
J Toppari ◽  
NE Skakkebaek
Keyword(s):  
Hypogonadotropic Hypogonadism ◽  
Serum Testosterone ◽  
Postnatal Period ◽  
Inhibin B ◽  
Testicular Growth ◽  
Normal Limits ◽  
Postnatal Treatment ◽  
Serum Hormone ◽  
Fertility Potential ◽  
Recombinant Human Fsh

BACKGROUND: Patients with hypogonadotropic hypogonadism may be diagnosed shortly after birth because of micropenis and cryptorchidism, combined with subnormal LH and FSH concentrations during the postnatal period. OBJECTIVE: To investigate whether treating these patients with gonadotropins postnatally, to mimic the physiological development, would improve testicular growth and fertility potential later in life. DESIGN: Our patient presented with micropenis. Serum hormone concentrations were measured monthly after delivery: LH and testosterone were undetectable, and FSH and inhibin B were below the normal range (0.05-0.17 IU/l and 79-112 pg/ml respectively). METHODS: From 7.9 to 13.7 months of age, the patient was treated with recombinant human LH and FSH in doses of 20 and 21.3 IU s.c. twice weekly respectively. RESULTS: During treatment concentrations of LH, FSH, inhibin B and estradiol increased to values within normal limits (0.7-1.88 IU/l, 0.17-3.24 IU/l, 121-268 pg/ml and 40-55 pmol/l respectively), whereas serum testosterone remained undetectable. Penile length increased from 1.6 to 2.4 cm and testicular volume, assessed by ultrasound, increased by 170%. No significant adverse events were observed. CONCLUSIONS: Gonadotropin treatment in an infant with hypogonadotropic hypogonadism succeeded in inducing an increase in inhibin B and testicular growth.

scholarly journals Larger Testes and Higher Inhibin B Levels in Finnish than in Danish Newborn Boys

2006 ◽  
Vol 91 (7) ◽  
pp. 2732-2737 ◽  
Author(s):  
Katharina M. Main ◽  
Jorma Toppari ◽  
Anne-Maarit Suomi ◽  
Marko Kaleva ◽  
Marla Chellakooty ◽  
...  
Keyword(s):  
Sperm Quality ◽  
Genetic Difference ◽  
Reproductive Hormones ◽  
Inhibin B ◽  
Testicular Volume ◽  
Seminiferous Tubules ◽  
Testicular Development ◽  
Testis Size ◽  
University Hospitals ◽  
Prospective Longitudinal

Abstract Context: Recent studies showed that male reproductive health problems, such as cryptorchidism, hypospadias, testicular cancer, and low sperm quality, are more prevalent in Denmark than in Finland. Objectives: We hypothesized that, if fetal testicular dysgenesis contributed to these observations, differences in gonadal development and the hypothalamus-pituitary-testis axis would already be detectable perinatally. Thus, we investigated healthy newborn boys in both countries. Design: This was a prospective, longitudinal population-based study. Setting: Two primary obstetric centers were included at the University Hospitals of Copenhagen, Denmark, and Turku, Finland. Participants: The participants of the study included 633 Danish and 1044 Finnish boys, born at term with appropriate weight for gestational age. Interventions: Ultrasound determination of testis size at 0, 3, and 18 months and blood sampling (n = 727) at 3 months were analyzed. Main Outcome Measures: Testicular volume and reproductive hormones were measured. Results: Testis volume was significantly higher at all ages in Finnish than in Danish boys (medians, 98 vs. 95, 185 vs. 119, and 188 vs. 136 mm3, respectively; P &lt; 0.00001). Testis growth from birth to 3 months was larger in Finnish than in Danish boys (mean, 75 vs. 26 mm3; P &lt; 0.0001). Serum hormone levels were higher in Finnish than Danish boys for inhibin B (median, 456 vs. 385 pg/ml; P &lt; 0.0001), FSH (1.33 vs. 1.21 IU/liter; P &lt; 0.036), and SHBG (143 vs. 136 nmol/liter; P &lt; 0.022). Inhibin B was significantly positively correlated to testicular volume (r = 0.25; P &lt; 0.006). Conclusions: The larger testes and higher inhibin B levels most likely represent a bigger volume of seminiferous tubules in Finnish compared with Danish boys. Although this phenomenon may be attributable to a genetic difference between the two countries, it may also reflect environmental factors influencing testicular development.

scholarly journals Effect of sialylation and complexity of FSH oligosaccharides on inhibin production by granulosa cells

Reproduction ◽  
2013 ◽  
Vol 145 (2) ◽  
pp. 127-135 ◽  
Author(s):  
Nazareth Loreti ◽  
Verónica Ambao ◽  
Luz Andreone ◽  
Romina Trigo ◽  
Ursula Bussmann ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Concanavalin A ◽  
Inhibin B ◽  
Inhibin A ◽  
Biological Responses ◽  
Immature Rats ◽  
Fold Stimulation ◽  
Recombinant Human Fsh

Granulosa cell (GC) inhibin A and B production is regulated by FSH and gonadal factors. This gonadotrophin is released as a mixture of glycoforms, which induce different biological responses in vivo and in vitro. Our aim was to determine the effect of recombinant human FSH (rhFSH) glycosylation variants on inhibin A and B production by rat GCs. Preparative isoelectro focusing was used to isolate more acidic/sialylated (pH <4.00) and less acidic/sialylated (pH >5.00) rhFSH charge analogues. Concanavalin A was used to isolate unbound and firmly bound rhFSH glycoforms on the basis of their oligosaccharide complexity. GCs, obtained from oestrogen-primed immature rats, were cultured with either native rhFSH or its glycosylation variants. Inhibin A and B were determined using specific ELISAs. Results were expressed as mean±s.e.m. Under basal conditions, inhibin A was the predominant dimer produced (inhibin A: 673±55; inhibin B: 80±4 pg/ml). More acidic/sialylated charge analogues stimulated inhibin B production when compared to inhibin A at all doses studied; by contrast, less acidic/sialylated charge analogues stimulated inhibin A production and elicited no effect on inhibin B. Glycoforms bearing complex oligosaccharides showed a potent stimulatory effect on inhibin B when compared to inhibin A production (i.e. dose 1 ng/ml: 4.9±0.5 vs 0.9±0.1-fold stimulation, P<0.001). Glycoforms bearing hybrid-type oligosaccharides favoured inhibin A production (i.e. dose 4 ng/ml 2.9±0.1 vs 1.6±0.1-fold stimulation, P<0.05). These results show that the sialylation degree as well as the complexity of oligosaccharides present in the rhFSH molecule may be considered additional factors that differentially regulate dimeric inhibin production by rat GCs.

Aurora a kinase (AURKA) is required for male germline maintenance and regulates sperm motility in the mouse

2021 ◽  
Author(s):  
William C Lester ◽  
Taylor Johnson ◽  
Ben Hale ◽  
Nicholas Serra ◽  
Brian Elgart ◽  
...  
Keyword(s):  
Cell Division ◽  
Sperm Count ◽  
Mitotic Cell ◽  
Vital Role ◽  
Conditional Knockout ◽  
Testis Size ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Mitotic Kinase ◽  
Knockout Animals

Abstract Aurora A kinase (AURKA) is an important regulator of cell division and is required for assembly of the mitotic spindle. We recently reported the unusual finding that this mitotic kinase is also found on the sperm flagellum. To determine its requirement in spermatogenesis, we generated conditional knockout animals with deletion of the Aurka gene in either spermatogonia or spermatocytes to assess its role in mitotic and postmitotic cells, respectively. Deletion of Aurka in spermatogonia resulted in disappearance of all developing germ cells in the testis, as expected given its vital role in mitotic cell division. Deletion of Aurka in spermatocytes reduced testis size, sperm count, and fertility, indicating disruption of meiosis or an effect on spermiogenesis in developing mice. Interestingly, deletion of Aurka in spermatocytes increased apoptosis in spermatocytes along with an increase in the percentage of sperm with abnormal morphology. Despite the increase in abnormal sperm, sperm from spermatocyte Aurka knockout mice displayed increased progressive motility. In addition, sperm lysate prepared from Aurka knockout animals had decreased protein phosphatase 1 (PP1) activity. Together, our results show that AURKA plays multiple roles in spermatogenesis, from mitotic divisions of spermatogonia to sperm morphology and motility.

scholarly journals Functional Hypogonadotropic Hypogonadism in Men: Underlying Neuroendocrine Mechanisms and Natural History

2019 ◽  
Vol 104 (8) ◽  
pp. 3403-3414 ◽  
Author(s):  
Andrew A Dwyer ◽  
Niraj R Chavan ◽  
Hilana Lewkowitz-Shpuntoff ◽  
Lacey Plummer ◽  
Frances J Hayes ◽  
...  
Keyword(s):  
Weight Loss ◽  
Natural History ◽  
Medical Center ◽  
Semen Analysis ◽  
Hypogonadotropic Hypogonadism ◽  
Academic Medical Center ◽  
Early Puberty ◽  
Hypothalamic Amenorrhea ◽  
Excessive Exercise ◽  
Neuroendocrine Mechanisms

Abstract Context After completion of puberty a subset of men experience functional hypogonadotropic hypogonadism (FHH) secondary to excessive exercise or weight loss. This phenomenon is akin to hypothalamic amenorrhea (HA) in women, yet little is known about FHH in men. Objective To investigate the neuroendocrine mechanisms, genetics, and natural history underlying FHH. Design Retrospective study in an academic medical center. Participants Healthy postpubertal men presenting with symptoms of hypogonadism in the setting of excessive exercise (>10 hours/week) or weight loss (>10% of body weight). Healthy age-matched men served as controls. Interventions Clinical assessment, biochemical and neuroendocrine profiling, body composition, semen analysis, and genetic evaluation of genes known to cause isolated GnRH deficiency. Main Outcome Measures Reproductive hormone levels, endogenous GnRH-induced LH pulse patterns, and rare genetic variants. Results Ten men with FHH were compared with 18 age-matched controls. Patients had significantly lower body mass index, testosterone, LH, and mean LH pulse amplitudes yet normal LH pulse frequency, serum FSH, and sperm counts. Some patients exhibited nocturnal, sleep-entrained LH pulses characteristic of early puberty, and one FHH subject showed a completely apulsatile LH secretion. After decreased exercise and weight gain, five men with men had normalized serum testosterone levels, and symptoms resolved. Rare missense variants in NSMF (n = 1) and CHD7 (n = 1) were identified in two men with FHH. Conclusions FHH is a rare, reversible form of male GnRH deficiency. LH pulse patterns in male FHH are similar to those observed in women with HA. This study expands the spectrum of GnRH deficiency disorders in men.

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