Activin and inhibin

Activin and inhibin are two closely related

Below is a list of the most common inhibin and activin complexes and their subunit composition:

Class Activity Complex Dimer subunits 1 2 Inhibin inhibits FSH secretion Inhibin A α βA Inhibin B α βB Activin stimulates FSH secretion Activin A βA βA Activin AB βA βB Activin B βB βB

The alpha and beta subunits share approximately 25% sequence similarity, whereas the similarity between beta subunits is approximately 65%.^[9]

In mammals, four beta subunits have been described, called activin β_A, activin β_B, activin β_C and activin β_E. Activin β_A and β_B are identical to the two beta subunits of inhibin. A fifth subunit, activin β_D, has been described in Xenopus laevis. Two activin β_A subunits give rise to activin A, one β_A, and one β_B subunit gives rise to activin AB, and so on. Various, but not all theoretically possible, heterodimers have been described.^[11][12] The subunits are linked by a single covalent disulfide bond.

The β_C subunit is able to form activin heterodimers with β_A or β_B subunits but is unable to dimerize with inhibin α.^[13]

Function

Activin

Activin is produced in the gonads, pituitary gland, placenta, and other organs:

• 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.
• Activin is strongly expressed in wounded
  epidermis of transgenic mice improves wound healing and enhances scar formation. Its action in wound repair and skin morphogenesis is through stimulation of keratinocytes and stromal cells in a dose-dependent manner.^[14]
• Activin also regulates the
  type-I collagen suggesting that activin A acts as a potent activator of fibroblasts
  .
• Lack of activin during development results in neural developmental defects.
• Upregulation of Activin A drives pluripotent stem cells into a mesoendodermal fate, and thus provides a useful tool for stem cell differentiation and organoid formation.^[15]

Inhibin

In both females and males, inhibin inhibits FSH production. Inhibin does not inhibit the secretion of GnRH from the hypothalamus.^[16][17] However, the overall mechanism differs between the sexes:

In females

Inhibin is produced in the

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

It is secreted from the

• Activin type 1 receptors: ACVR1, ACVR1B, ACVR1C
• Activin type 2 receptors: ACVR2A, ACVR2B

Activin binds to the Type II receptor and initiates a cascade reaction that leads to the recruitment, phosphorylation, and activation of Type I activin receptor. This then interacts with and then phosphorylates SMAD2 and SMAD3, two of the cytoplasmic SMAD proteins.

Smad3 then translocates to the nucleus and interacts with SMAD4 through multimerization, resulting in their modulation as transcription factor complexes responsible for the expression of a large variety of genes.

Inhibin

In contrast to activin, much less is known about the mechanism of action of inhibin, but may involve competing with activin for binding to activin receptors and/or binding to inhibin-specific receptors.^[8]

Clinical significance

Activin

Activin A is more plentiful in the adipose tissue of obese, compared to lean persons.^[20] Activin A promotes the proliferation of adipocyte progenitor cells, while inhibiting their differentiation into adipocytes.^[20] Activin A also increases inflammatory cytokines in macrophages.^[20]

A

Mutations in the ACVR1 gene have also been linked to cancer, especially diffuse intrinsic pontine glioma(DIPG).^[23][24][25]

Elevated Activin B levels with normal Activin A levels provided a possible biomarker for myalgic encephalomyelitis/chronic fatigue syndrome.^[26]

Activin A is overexpressed in many cancers. It was shown to promote tumorigenesis by hampering the adaptive anti-tumor immune response in melanoma.^[27]

Inhibin

Quantification of inhibin A is part of the prenatal

It also has been used as a marker for ovarian cancer.^[29][30]

Inhibin B may be used as a marker of spermatogenesis function and male infertility. The mean serum inhibin B level is significantly higher among fertile men (approximately 140 pg/mL) than in infertile men (approximately 80 pg/mL).^[31] In men with azoospermia, a positive test for inhibin B slightly raises the chances for successfully achieving pregnancy through testicular sperm extraction (TESE), although the association is not very substantial, having a sensitivity of 0.65 (95% confidence interval [CI]: 0.56–0.74) and a specificity of 0.83 (CI: 0.64–0.93) for prediction the presence of sperm in the testes in non-obstructive azoospermia.^[32]

References