Activin and inhibin

Activin and inhibin are two closely related protein complexes that have almost completely opposite biological effects. Activin increases the biosynthesis and secretion of FSH, and participates in the regulation of the menstrual cycle. Many other functions have been found to be exerted by activin, including its role in cell proliferation, cell differentiation, apoptosis, metabolism, homeostasis, immune response, wound healing, and endocrine function. Conversely, inhibin downregulates FSH synthesis and inhibits FSH secretion.

Activin is a dimer composed of two identical or very similar beta subunits. Inhibin is also a dimer where the first component is a beta subunit similar or identical to the beta subunit in activin. Unlike activin, however, the second component of the inhibin dimer is more of a distantly-related alpha subunit. Activin, inhibin, and a number of other structurally related proteins such as anti-Müllerian hormone, bone morphogenic protein, and differentiation growth factor belong to the TGF-β superfamily of proteins.

Structure

The activin and inhibin protein complexes are both dimeric in structure, and, in each complex, two monomers are linked to each other by a disulfide bond. complexes are derived from the same family of genes and related proteins but differ in their subunit composition. Below is a list of the most common inhibin and activin complexes and their subunit composition:

Class Activity Complex Dimera subunits 1 2 Inhibin inhibits the secretion of FSH Inhibit A α βA B inhibitor α βB Activina stimulates the secretion of FSH Activina A βA βA Activine AB βA βB Activina B βB βB

Schematic diagram of the 1D structures of the inhibitor and activine. The black line between monomers represents a disulfuriate link.

The alpha and beta subunits share approximately 25% sequence similarity, while the similarity between the beta subunits is approximately 65%.

Four beta subunits have been described in mammals, 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 subunit, and one β_B subunit give rise to activin AB, and so on. Several heterodimers have been described, but not all that are theoretically possible. The subunits are linked by a single disulfide covalent bond.

The βC subunit is capable of forming activin heterodimers with β_A or β_B subunits, but is not capable of dimerization with α inhibin.

Function

Activin

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

• In the ovarian follicle, the activine increases the union of the FSH and the aromatization induced by the FSH. It participates in androgen synthesis by enhancing the action of LH in ovary and testicles. In man, activine enhances spermatogenesis.

• Activine is strongly expressed in the wounds of the skin, and overexpression of activine in the epidermis of transgenic mice improves wound healing and enhances scar formation. Its action in healing wounds and morphogenesis of the skin is through the stimulation of keratinocyte and estromal cells in a dose-dependent manner.

• Activine also regulates the morphogenesis of branching organs such as prostate and especially kidney. Activine A increases the expression levels of type I collagen suggesting that activine A acts as a powerful fibroblast activator.

• Lack of activine during development results in neural development defects.

Inhibin

In both women and men, inhibin inhibits FSH production and GnRH release from the hypothalamus. However, the mechanism in general differs between the sexes.

In women

Inhibin is produced in the gonads, pituitary gland, placenta, and other organs.

In women, FSH stimulates the secretion of inhibin from the granulosa cells of the ovarian follicle in the ovaries. In turn, inhibin suppresses FSH.

• La inhibitor B reaches a maximum in the early and mid follicular phase, and reaches a second maximum in ovulation.

• La inhibitor A reaches its peak in the middle of the lutea phase.

Inhibin secretion is decreased by GnRH, and increased by insulin-like growth factor 1 (IGF-1).

In men

Inhibin is secreted from Sertoli cells, located in the seminiferous tubules within the testes. Androgens stimulate inhibin production; this peptide could also locally regulate spermatogenesis.

Mechanism of action

Activin

Like other members of the superfamily, activins interact with two types of transmembrane receptors (Type I and II) that have intrinsic serine/threonine kinase activities in their cytoplasmic domains:

• Type 1: ACVR1, ACVR1B, ACVR1C
• Type 2: ACVR2A, ACVR2B

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

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 wide variety of genes. Activin is inhibited by members of the Smad family, including Smad7.

Inhibin

Unlike activin, much less is known about inhibin's mechanism of action, but it could involve competition with activin to bind to activin receptors and/or bind to specific inhibin receptors.

Medical relevance

Inhibin A quantification is part of the triple test prenatal test that can be administered during pregnancy at a gestational age of 16-18 weeks. Elevated inhibin A (along with increased beta-hCG, decreased AFP, and decreased estriol) is suggestive of the presence of a fetus with Down syndrome. As a screening test, abnormal results need a follow-up. follow up with more definitive tests.

It has also been used as a marker of ovarian cancer.

Inhibin B could be used as a marker of spermatogenesis function and male sterility. Average inhibin B levels are significantly higher among fertile men (approximately 140 pg/mL) than infertile men (approximately 80 pg/mL). In men with azoospermia, a positive inhibin B test slightly increases the odds of achieve a successful pregnancy through testicular sperm extraction (TESE), although the association is not very substantial, with 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 predicting the presence of sperm in the testes in non-obstructive azoospermia.