Inhibin-B: a likely candidate for the physiologically important form of inhibin in men

Illingworth, Peter

doi:10.1210/jc.81.4.1321

Cited by 170 publications

(132 citation statements)

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“…Others have previously demonstrated a ‘feed-forward’ relationship between FSH and I B during the earliest stages of pubertal development wherein FSH secretion drives I B secretion from the Sertoli cells [40]. However, once the first wave of spermatogenesis has occurred, a negative feedback loop between I B secretion and FSH is subsequently activated [40,41,42,43,44] that suppresses subsequent FSH release from the gonadotropes. Therefore, in our subjects with absent puberty, low I B levels may be responsible for the relatively unconstrained FSH responsiveness in Group I who reflect the earliest stages of pubertal development.…”

Section: Discussionmentioning

confidence: 99%

Role of Seminiferous Tubular Development in Determining the FSH versus LH Responsiveness to GnRH in Early Sexual Maturation

Pitteloud¹,

Thambundit²,

Dwyer³

et al. 2009

Neuroendocrinology

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Background: The onset of sexual maturation at puberty is a unique developmental period from a neuroendocrine perspective in that it is characterized by enhanced FSH secretion and FSH responsiveness to exogenous GnRH (vs. LH) from the gonadotrope, yet the mechanism of these dynamics remains unclear. This study aimed to elucidate this phenomenon using a human disease model of GnRH deficiency (idiopathic hypogonadotropic hypogonadism, IHH) in which GnRH input can be experimentally controlled. Methods: 25 GnRH-deficient men were selected for study based upon their baseline testicular volumes (TV) and serum inhibin B (I_B) levels to represent a spectrum of pubertal/testicular development. Subjects underwent: (i) a 12-hour overnight neuroendocrine evaluation for hormonal profiling and determination of endogenous LH secretion pattern, and (ii) a 7-day exposure to a physiologic regimen of exogenous pulsatile GnRH (25 ng/kg every 2 h). Daily measurements of serum testosterone (T) and I_B levels were made and a 2-hour window of frequent blood sampling was monitored to measure LH and FSH following a single i.v. GnRH bolus (25 ng/kg). All subjects were screened for known loci underlying GnRH deficiency and the response to GnRH was tracked according to genotype. Results: Among the entire cohort, no changes were noted in serum T or I_B during the 7 days, thus keeping gonadal feedback relatively constant. However, serum LH and FSH levels increased significantly (p < 0.0001) in the entire cohort. When analyzed by degree of pubertal/testicular development, men with no evidence of prior spontaneous pubertal development (TV ≤3 ml, Group I) showed sharp increases in serum FSH compared to men with some prior evidence of partial puberty (TV >3 ml, Group II, p < 0.0001). Group I exhibited a decreased LH response to GnRH on day 2 compared to day 1 (p < 0.01), which did not recover until day 5 (1–4 vs. 5–7 days, p < 0.0001). Group II displayed robust and equivalent LH responses to GnRH throughout the 7-day study. Genetic studies identified 8 mutations in 4 different loci (DAX1, KAL1, GNRHR, and FGFR1) in this cohort. Conclusions: GnRH-deficient men undergoing GnRH-induced sexual maturation display an inverse relationship between FSH responsiveness to GnRH and baseline testicular size and I_B levels. This observation implies that increasing seminiferous tubule maturity represents the major constraint on FSH responsiveness to GnRH in early puberty. In contrast, LH responsiveness to GnRH correlates directly with duration of GnRH exposure. Attenuated pituitary gonadotropin responses were noted in subjects harboring DAX1 mutations, consistent with known pituitary defects.

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Section: Discussionmentioning

confidence: 99%

Role of Seminiferous Tubular Development in Determining the FSH versus LH Responsiveness to GnRH in Early Sexual Maturation

Pitteloud¹,

Thambundit²,

Dwyer³

et al. 2009

Neuroendocrinology

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“…The negative feedback inhibition of gonadal hormones on FSH secretion involves both gonadal peptides (inhibin, activin) and steroid hormones (testosterone and estradiol). On the other hand, FSH and androgen are necessary for normal inhibin production by gonadal tissues [19]. …”

Section: Discussionmentioning

confidence: 99%

An Inhibin B and Estrogen-Secreting Adrenocortical Carcinoma Leading to Selective FSH Suppression

et al. 2006

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Objective: Hormone-secreting adrenocortical tumors are frequently associated with endocrine syndromes. We describe a 30-year-old man who had abdominal pain, a nodule in the right breast and loss of libido. Abdominal magnetic resonance imaging revealed a very large tumor in the right adrenal gland. Methods: Hormonal profile disclosed increased levels of estradiol and slightly low testosterone levels. The basal and stimulated LH levels were normal, whereas basal and stimulated FSH levels were totally suppressed. Cortisol and adrenal androgen levels were normal. The unusual finding of selective FSH suppression suggested secretion of inhibin B by the adrenocortical tumor. A very high level of serum inhibin B (405 pg/ml) was demonstrated by ELISA assay. Right adrenalectomy and nephrectomy were performed and the tumor was classified as a malignant tumor (Weiss score: 7.0) and unilateral mastectomy disclosed a lipoma. Results: One week after surgery, a GnRH-stimulation test disclosed normal basal and stimulated FSH levels and low levels of inhibin B and estradiol. Immunohistochemical analysis with anti-B-inhibin antibody revealed intense staining in the adrenocortical tumor cells. One month after surgery, an abdominal magnetic resonance imaging revealed a local recurrence of the tumor and a second surgery was performed with partial resection of the tumor and the patient died 1 year after the first surgery. Conclusion: We herein report the first inhibin B and estradiol-secreting adrenocortical carcinoma. The unusual selective inhibition of FSH secretion should be considered a valuable hormonal finding for the diagnosis of inhibin B-secreting adrenocortical tumors.

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“…Alternatively, long-term GH deficiency may have caused irreversible changes in the germinative epithelium. Circulating inhibin-B is the physiologically important form of inhibin in men [28] and is produced by the Sertoli cells and stimulated by gonadotropins. Inhibin-B is involved in the feedback regulation of pituitary FSH secretion and there is an inverse relationship between inhibin-B and FSH levels in healthy adult males [28].…”

Section: Discussionmentioning

confidence: 99%

“…Circulating inhibin-B is the physiologically important form of inhibin in men [28] and is produced by the Sertoli cells and stimulated by gonadotropins. Inhibin-B is involved in the feedback regulation of pituitary FSH secretion and there is an inverse relationship between inhibin-B and FSH levels in healthy adult males [28]. Earlier assays to determine inhibin were unable to distinguish between inhibin A and B, and crossreacted with bioinactive inhibin precursors.…”

Section: Discussionmentioning

confidence: 99%

Effects of Growth Hormone Replacement Therapy on IGF-Related Parameters and on the Pituitary-Gonadal Axis in GH-Deficient Males

et al. 1998

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It has been suggested that growth hormone (GH) may play a regulatory role in male reproductive function. To express full anabolic effect in immature boys testosterone apparently requires the presence of GH. In GH-deficient adults, GH replacement therapy exerts a variety of anabolic actions, some of which are similar to the effects of gonadal steroids. However, little is known about the potential effects of GH on gonadal steroids and on dynamic tests of pituitary-gonadal function in adults with GH deficiency. We evaluated the pituitary-gonadal axis in a 4-month double-blind, placebo-controlled GH study in 13 young males with childhood-onset GH deficiency of which 6 had isolated GH deficiency. GH treatment significantly increased serum levels of total IGF-I from 98 (68) to 323 (126) µg/l, free IGF-I from 0.48 (0.47) to 2.24 (1.66) µg/l, IGFBP-3 from 1,874 (1,178) to 3,520 (778) µg/l and ALS levels from 9,182 (5,524) to 16,872 (6,278) µg/l (all p < 0.0001). We found no differences in basal testosterone levels in the 13 patients between the GH and placebo treatment periods (21.9 (5.1) vs. 24.5 (8.1) nmol/l, nonsignificant). Furthermore, no effect of GH on the testicular response to hCG after 72 h was seen compared to placebo (36.2 (6.4) vs. 38.8 (10.3) nmol/l). In addition, no differences existed in basal SHBG, DHT, free testosterone, Δ4-adion and DHEA-S levels. There were no statistically significant differences in maximal FSH and LH response to a GnRH challenge between the GH and the placebo periods (15.7 (5.3) vs. 18.0 (8.8) U/l and 47.0 (26.4) vs. 40.4 (26.5) U/l, respectively). Furthermore, there was no effect on cortisol responses after ACTH between the GH and the placebo periods. However, significantly higher estradiol levels were seen after GH treatment (110 (50) pmol/l) compared to after placebo (89 (34) pmol/l, p = 0.03). Prostate-specific antigen levels decreased after GH treatment compared to after placebo (0.42 (0.54) vs. 0.47 (0.48) µg/l) and this difference almost reached statistical significance (p = 0.059). Inhibin-B levels were significantly lower in hypogonadal patients substituted with androgens, but GH had no effect on inhibin-B levels. In conclusion, GH replacement therapy in 13 GH-deficient young adult males resulted in significant increases in total and free IGF-I as well as in ALS levels in all patients, but had no significant effect on: (1) the pituitary FSH and LH response to GnRH; (2) basal and hCG-stimulated levels of androgens and SHBG; (3) basal inhibin-B levels; (4) ACTH-stimulated cortisol secretion. By contrast, GH administration had subtle anti-androgenic effects in terms of elevated elevated estradiol levels and decreased prostate-specific antigen levels, although both parameters remained within the normal range. Thus, at the level of blood chemistry the effects of GH administration do not appear to involve major alterations in the pituitary-gonadal axis.

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Inhibin-B: a likely candidate for the physiologically important form of inhibin in men

Cited by 170 publications

References 0 publications

Role of Seminiferous Tubular Development in Determining the FSH versus LH Responsiveness to GnRH in Early Sexual Maturation

Role of Seminiferous Tubular Development in Determining the FSH versus LH Responsiveness to GnRH in Early Sexual Maturation

An Inhibin B and Estrogen-Secreting Adrenocortical Carcinoma Leading to Selective FSH Suppression

Effects of Growth Hormone Replacement Therapy on IGF-Related Parameters and on the Pituitary-Gonadal Axis in GH-Deficient Males

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