Table of Contents
follicle stimulating hormone (FSH)
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Introduction
- FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and, along with luteinizing hormone (LH), regulates the development, growth, pubertal maturation, and reproductive processes of the body, and in particular, stimulates the maturation of primordial germ cells required for ovulation and spermatogenesis.
- FSH is a 35.5 kDa glycoprotein heterodimer, consisting of two polypeptide units, alpha and beta. Its structure is similar to those of luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and human chorionic gonadotropin (hCG)
- The alpha subunits of the glycoproteins LH, FSH, TSH, and hCG are identical and consist of 96 amino acids, while the beta subunits vary.
- FSH has a beta subunit of 111 amino acids (FSH β), which confers its specific biologic action, and is responsible for interaction with the follicle-stimulating hormone receptor.
- the gene for the alpha subunit is located at cytogenetic location 6q14.3 and is expressed in two cell types, most notably the basophils of the anterior pituitary
- the gene for the FSH beta subunit is located on chromosome 11p13, and is expressed in gonadotropes of the pituitary cells, controlled by GnRH, inhibited by inhibin, and enhanced by activin
Control of FSH secretion
- GnRH has been shown to play an important role in promoting the secretion of FSH and LH from the anterior pituitary
- GnRH administration leads to a return of FSH secretion.
- GnSAF is functionally antagonistic to GnRH over the control of LH secretion and keeps the anterior pituitary in a low responsiveness state, which prevents acute elevations of serum LH concentrations until GnSAF bioactivity declines
- when oestradiol concentrations are high in the late follicular phase, GnRH pulse frequency and amplitude increases and overrides the attenuating effects of GnSAF on suppression of LH secretion
- FSH secretion is subject to negative oestrogen feed-back from the gonads via the hypothalamic pituitary gonadal axis.
- inhibin downregulates FSH synthesis and inhibits FSH secretion.
- in females, inhibin is produced in the gonads, pituitary gland, placenta, corpus luteum and other organs
- FSH stimulates the secretion of inhibin from the granulosa cells of the ovarian follicles in the ovaries. In turn, inhibin suppresses FSH.
- inhibin B reaches a peak in the early- to mid-follicular phase, and a second peak at ovulation.
- inhibin A reaches its peak in the mid-luteal phase.
- inhibin secretion is diminished by GnRH, and enhanced by insulin-like growth factor-1 (IGF-1).
- in males, inhibin is secreted from the Sertoli cells
- androgens stimulate inhibin production
- activin stimulates FSH secretion
- In the ovarian follicle, activin increases FSH binding and FSH-induced aromatization. It participates in androgen synthesis enhancing LH action in the ovary and testis.
- In the male, activin enhances spermatogenesis.
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- spermatogenesis
- FSH induces Sertoli cells to secrete androgen-binding proteins (ABPs), regulated by inhibin's negative feedback mechanism on the anterior pituitary. Specifically, activation of Sertoli cells by FSH sustains spermatogenesis and stimulates inhibin B secretion.
- ovulation
- early follicular phase and development of small antral follicles:
- FSH initiates follicular growth, specifically affecting granulosa cells.
- FSH induces expression and transcription of exons 12 and 13 of the HSA gene (gene for GnSAF) in granulosa cells.
- FSH stimulates and prolongs gonadotropin surge-attenuating factor (GnSAF) biosynthesis in growing small antral follicles in the ovary.
- GnSAF exerts a negative feedback on pulsatile luteinizing hormone (LH) secretion amplitude, thus allowing a more favorable environment for follicle growth and preventing premature luteinization
- higher serum concentrations of FSH increases the potency of the attenuating effects of GnSAF on the release of LH.
- FSH controls follicular fluid (FF) glutamine levels which in turn regulates GC apoptosis via the ASK1-JNK pathway 1)
- FSH plays a pivotal role in directing granulosa cell glutamine synthesis, which is essential for follicle development and the regulation of ovulation.
- FSH promotes the synthesis of glutamine in granulosa cells, leading to increased glutamine levels in the follicular fluid.
- late follicular phase and formation of dominant follicle with atresia of other follicles
- when the follicle matures and reaches 8–10 mm in diameter it starts to secrete significant amounts of oestradiol.
- normally in humans only one follicle becomes dominant and survives to grow to 18–30 mm in size and ovulate, the remaining follicles in the cohort undergo atresia. The sharp increase in oestradiol production by the dominant follicle (possibly along with a decrease in GnSAF) cause a positive effect on the hypothalamus and pituitary and rapid GnRH pulses occur and an LH surge results.
- occasionally two follicles reach the 10 mm stage at the same time by chance and as both are equally sensitive to FSH both survive and grow in the low FSH environment and thus two ovulations can occur in one cycle possibly leading to non-identical (dizygotic) twins
- with the concomitant rise in inhibin B, FSH levels then decline in the late follicular phase. This seems to be critical in selecting only the most advanced follicle to proceed to ovulation.
- without the presence of small follicles during the late follicular phase, GnSAF concentrations steadily decline to its lowest levels observable in the ovarian cycle
- as FSH levels decrease, the supply of glutamine in the follicular fluid diminishes, resulting in the apoptosis of granulosa cells. This process contributes to the breakdown of the follicle wall from the inside out, which is a crucial step in ovulation.
- patients with polycystic ovary syndrome (PCOS) / polyendocrine metabolic ovarian syndrome (PMOS) have elevated glutamine levels in their follicular fluid compared to non-PCOS individuals suggesting dysregulated glutamine levels play a key role.
- supraphysiological concentrations of oestradiol maintains high pituitary responsiveness to GnRH, permitting the hypersecretion of LH
- many have higher GnRH pulse frequency and tonic hypersecretion of LH due to hypersecretion of androgens from the polycystic ovary (androgens are converted to oestrogens in the ovaries).
- hypersecretion of LH contributes to cycle disturbance, infertility and increased chances of miscarriage.
- mid-cycle
- the absence of GnSAF lowers the threshold for GnRH pulse frequency and amplitude required to stimulate the anterior pituitary to secrete LH creating a LH surge lasting 48 to 72 hours
- meiosis in the dominant follicle resumes and the follicle ruptures shortly after the LH surge resulting in ovulation.
- ovulation can only occur if GnSAF is absent and the mid-cycle LH surge occurs
- early luteal phase
- oestradiol concentrations drop and the corpus luteum develops
- FSH does not stimulate GnSAF production in the corpus luteum, so GnSAF bioactivity is low after ovulation, until the intercycle rise in FSH occurs
- end of luteal phase
- the serum levels of progesterone and oestrogen (primarily oestradiol) decrease and no longer suppress the release of FSH, consequently FSH peaks at about day three (day one is the first day of menstrual flow)
- this results in a slight rise in FSH that seems to be of importance to start the next ovulatory cycle.
- GnSAF gradually increases from the late luteal phase and onwards due to the recruitment of follicles and concomitant rise of FSH
- perimenopause
- As a woman nears perimenopause, the number of small antral follicles recruited in each cycle diminishes and consequently insufficient Inhibin B is produced to fully lower FSH and the serum level of FSH begins to rise. Eventually, the FSH level becomes so high that downregulation of FSH receptors occurs and by postmenopause any remaining small secondary follicles no longer have FSH nor LH receptors 2)