Inhibin-A and inhibin-B in cyclic and pregnant mares, and mares with granulosa-theca cell tumors: Physiological and diagnostic implications

Abstract

Studies in mares have examined serum inhibin concentrations using immuno-assays unable to distinguish dimeric inhibin-A from inhibin-B isoforms. Inhibin-A and inhibin-B immuno-assays were used to investigate concentrations in cyclic mares, young and old (6 vs 19 years old, respectively) mares following hemi-ovariectomy, mares during pregnancy and in mares with confirmed granulosa cell tumors (GCTs). Mares with inter-ovulatory intervals of 26 days had ovulatory peaks of inhibin-A averaging 80 pg/mL with a mid-cycle nadir of 5 pg/mL. Inhibin-A and inhibin-B concentrations were highly correlated (r = + 0.79, P < 0.01) though peak and nadir concentrations of inhibin-B were not significantly different. However, the ratio of inhibin-A to inhibin-B (A/B) changed significantly through the cycle, highest at ovulation and <1 (more inhibin-B than -A) at mid-cycle. Two mares with grossly extended inter-ovulatory intervals demonstrated mid-cycle inhibin-A (and inhibin-B) excursions suggestive of follicular waves. Follicle-stimulating hormone was negatively correlated with inhibin-A and -B concentrations in all 6 mares. Hemi-ovariectomy in young mares resulted in a significant decrease in inhibin-A and inhibin-B concentrations one day later (P < 0.05) but older mares did not, suggesting a possible extra-ovarian source(s) of these hormones. Both inhibin isoforms dropped to very low levels during pregnancy (P < 0.0001), inhibin-A (P < 0.0001) more rapidly than -B (P < 0.05), so that inhibin-B became the predominant measured form throughout most of gestation (P < 0.05). Mares with confirmed GCTs had elevated inhibin-B concentrations more reliably than inhibin-A but neither inhibin-A or -B was correlated with anti-Müllerian hormone concentrations. Collectively, concentrations of inhibin-A and -B were aligned with physiological events in healthy mares, though more pronounced cyclic changes were seen with inhibin-A. Inhibin-B concentrations were significantly associated with GCTs (P < 0.01), inhibin-A concentrations were not. While both inhibin-A and -B concentrations track physiological events such as cyclic follicular activity, only inhibin-B concentrations effectively signal ovarian neoplasia in mares.

Equine granulosa cell tumours among other ovarian conditions: Diagnostic challenges

“…The confirmed and suspected GCTs were selected for their unusual presentation, and clinical and endocrinological progression. For instance, though most GCTs secrete increased concentrations of inhibins, 4 including inhibin B, 29 very few of the GCTs reported in this case series did. These cases are organised by ovarian size on initial clinical examination forming three groups of mares with, (a) a single, abnormally large ovary, (b) two abnormally large ovaries and (c) two ovaries of relatively normal size.…”

“…The concentration of ‘inhibins’ was increased on initial examination, but not thereafter, even though reportedly increased in normal pregnancies in mid to late gestation 43 . In contrast to ‘inhibins’, inhibin B 29 and AMH 23 are more reliable markers for GCTs, especially during pregnancy, though the current cases were not emblematic in this regard and were chosen for their unusual presentation and course. Indeed, AMH fluctuated markedly in this mare, from clearly increased (>10 ng/mL) on several occasions to within normal limits multiple times over the course of the year or more she was monitored (Figure 2), but was within normal limits at the time of surgery when the ovary was removed and the GCT was confirmed.…”

“…The original ‘inhibins’ immunoassay (developed for horses by Clinical Endocrinology Laboratory, UC Davis) that used antisera recognising parts of the common α‐subunit, cross‐reacted with some α‐subunit precursors 28 and therefore lacked specificity, even detecting free α‐subunit. Recently, assays specific for the inhibin‐A and inhibin B isoforms were validated for use in horses 29 . Inhibin B is secreted by equine GCTs, 29 and interestingly by the equine testis, 30,31 and this assay has replaced the nonspecific ‘inhibins’ immunoassay for diagnostic applications.…”

Anti-Müllerian hormone and ovarian aging in mares

“…Serum was harvested after centrifugation (1500 g for 10 min) and stored for analysis (−20°C). These samples were also included in a recently published, unrelated study evaluating inhibin-A and -B concentrations (Conley et al 2017). Unilateral ovariectomy was performed standing through a vertical flank incision of approximately 15 cm in length under sedation (detomidine, 20 μg/kg) and local anesthesia was induced by lidocaine infiltration.…”

Inhibin B suppresses anoikis resistance and migration through the transforming growth factor‐β signaling pathway in nasopharyngeal carcinoma

“…As one of the TGF‐β super‐family members, INHBB is commonly described as inhibitor of gonadal follicle‐stimulating hormone secretion, and INHBB has been evaluated for pregnancy‐related conditions and reproductive system tumors . Risbridger et al reported that INHB was elevated in testicular Sertoli cell tumor, adrenocortical carcinoma, and placental tumors, and lower in renal cell, hepatocellular, pancreatic, and prostate carcinomas.…”