Hallmarks of Human Small Antral Follicle Development: Implications for Regulation of Ovarian Steroidogenesis and Selection of the Dominant Follicle

Abstract

Regulation of human ovarian steroidogenesis differs from other species and precise knowledge on how human small antral follicles (hSAF) develop and acquire competence for continued growth and steroid output is still incomplete. The present study has characterized almost 1,000 normal hSAF collected in connection with cryopreservation of ovarian tissue for fertility preservation. The antral follicles (ranging from 3 to 13 mm) were generally aspirated from one ovary surgically removed during the natural cycle, and the follicular fluid (FF) and the granulosa cells (GC) were isolated and snap-frozen. In FF, the following hormones were measured: inhibin-B, inhibin-A, AMH, follistatin, PAPP-A, estradiol, progesterone, testosterone, and androstenedione. In GC, mRNA gene expressions using q-PCR were measured for the following genes: FSHR, AMH, CYP19, and AR. All samples in which one of the abovementioned parameters was measured were included, but typically multiple parameters were measured. Highly significant differences in concentration and follicular content in relation to follicular diameter were found for all measured hormones despite massive variability in-between follicles for any given diameter. The results demonstrate that profound changes take place in the hormonal microenvironment around follicular diameters of 8–11 mm corresponding to when follicular selection occurs. At this point, inhibin-B and inhibin-A showed distinct peaks concomitant with a significant reduction in both AMH protein and mRNA expression. Concentrations of inhibins, androgens, FSHR, and AR were intimately associated, and it is suggested that inhibin-B in combination with PAPP-A and thereby IGF2 activity exerts important paracrine signaling at follicular selection. At the same time upregulation of estradiol synthesis and CYP19 mRNA expression increased steroid output profoundly. Furthermore, the highly significant association between FSHR and AR mRNA gene expression enforces important functions of androgens in follicular development. Collectively, these data reintroduce the understanding of the follicular phase as two parted in which regulation of steroidogenesis differs. The profound changes taking place around follicular selection highlight important paracrine actions of TGF-β family members and IGFs for securing dominance of the selected follicle.

The ratio of exogenous Luteinizing hormone to Follicle stimulating hormone administered for controlled ovarian stimulation is associated with oocytes’ number and competence

“…In the primates' ovaries, the highest androgen receptor density was found in preantral and antral follicles [29], suggesting the importance of androgens in these stages of development. In humans, a recent study showed a strong association between androgen receptor and FSH receptor mRNA gene expression in antral follicles of 3-13 mm [30], supporting the existence of synergism between androgens and FSH action. Thus, according to these data, androgens are essential in early follicular phase for antral follicle growth and FSH-responsiveness and, therefore, the ovarian microenvironment characterized by higher androgens levels in patients receiving LH can contribute to a higher number of antral follicles available for recruitment under FSH stimulation in COS.…”

Inhibin as a reproductive biomarker. Part 1

“…По мере роста фолликула уровень ингибина А повышается постепенно, а при достижении фолликулом диаметра 13-14 мм его уровень резко повышается и концентрация превосходит концентрацию ингибина В [4]. Таким образом, уровень ингибина А значительно повышается в период резкого роста доминантного фолликула [6,44]. При этом уровень ингибина А коррелирует с уровнем эстрадиола и тестостерона [6].…”

“…Таким образом, уровень ингибина А значительно повышается в период резкого роста доминантного фолликула [6,44]. При этом уровень ингибина А коррелирует с уровнем эстрадиола и тестостерона [6]. Формирование желтого тела указывает на конец фолликулярного цикла, и если происходит [4].…”

“…Формирование желтого тела указывает на конец фолликулярного цикла, и если происходит [4]. Ингибин В в синергизме с ЛГ также участвует в паракринной модуляции продукции андрогенов (андростендиона и дегидроэпиандростерона), стимулируя клетки теки [4,6,[48][49][50]. Некоторые авторы считают, что ингибин не оказывает самостоятельного стимулирующего влияния на секрецию андрогенов, а действует исключительно путем подавления ингибирующего эффекта активина на секрецию андростендиона тека-клетками [49].…”

“…Сегодня ингибин описывают как гонадный гормон, снижающий секрецию фолликулостимулирующего гормона (ФСГ) передней доли гипофиза, а также как паракринный фактор, который регулирует фолликулогенез, стероидогенез яичников и сперматогенез [1][2][3][4][5][6]. Известно антагонистическое действие ингибина по отношению к другому пептидному гормону -активину.…”