Inhibin, activin and AMH
(endocrine regulation of follicular function)

Inhibins, activins and anti-Müllerian hormone (AMH) constitute a protein regulatory system that integrates ovarian physiology with the central control exerted by the hypothalamic-pituitary-gonadal axis. These factors are not ovarian steroids, but glycoproteins belonging to the TGF-β superfamily, and they act primarily as modulators of follicular growth and pituitary FSH secretion. Their physiological function is to coordinate the pace of folliculogenesis, maintain the balance between follicular recruitment and selection, and provide the pituitary with information about the functional status of the ovary.

The physiology of these molecules demonstrates that the ovary is a highly dynamic endocrine organ in which the regulation of reproductive function depends not only on sex steroids, but also on a network of protein signals operating at the paracrine, autocrine and endocrine levels. Inhibins and activins directly regulate pituitary gonadotropin secretion and modulate follicular sensitivity to FSH, while AMH controls the rate at which primordial follicles enter the growing pool. The result is a multilevel feedback system that connects the status of ovarian reserve with regulation of the central endocrine axis.

Follicular growth is a continuous process involving a population of follicles at different stages of development. At any given time, the ovary contains thousands of primordial follicles, but only a small fraction of them are recruited into growth. Among the follicles that reach the antral stage, only one becomes the dominant follicle and completes ovulatory maturation. This balance requires regulatory mechanisms that control initial recruitment, sensitivity to gonadotropins and competition among follicles.

The hypothalamic-pituitary-ovarian axis provides the gonadotropin signal required for follicular growth, but the local dynamics of folliculogenesis depend largely on paracrine signals produced by granulosa and theca cells. Among these factors, inhibins and activins modulate pituitary FSH secretion and the follicular response to the gonadotropin, while AMH regulates the rate at which primordial follicles enter the growth process.

This regulatory network creates a feedback system that connects the status of the follicular population with gonadotropin secretion. When numerous antral follicles are present, increased inhibin production reduces pituitary FSH secretion and limits the recruitment of new follicles. Conversely, activin production promotes FSH secretion and amplifies the follicular response to the gonadotropin. AMH instead acts as a negative modulator of initial recruitment and contributes to preserving ovarian reserve.

Three physiological principles govern follicular regulation mediated by these peptides:

• control of primordial follicle recruitment through the action of AMH;
• endocrine feedback on the pituitary through inhibins and activins that modulate FSH secretion;
• intraovarian paracrine regulation that modulates granulosa cell proliferation and sensitivity to gonadotropins.

This control system ensures that folliculogenesis proceeds at a rate compatible with the preservation of fertility over time and with the need to cyclically select a single dominant follicle.

Inhibins and activins are dimeric glycoproteins belonging to the TGF-β growth factor superfamily. These molecules share a structural organization based on protein subunits designated α and β, which form dimers stabilized by disulfide bonds. Different combinations of the subunits determine the biological properties of the mature molecules.

Inhibins are heterodimers composed of one α subunit and one β subunit. Two main isoforms are present in the human ovary: inhibin A and inhibin B. They differ in the β subunit involved and in the phase of the menstrual cycle during which their secretion predominates. Inhibin B is produced mainly by antral follicles during the early follicular phase, whereas inhibin A is secreted by the dominant follicle and the corpus luteum during the later stages of the cycle.

Activins, in contrast, are dimers composed exclusively of β subunits. The main identified isoforms are activin A, activin B and activin AB. These molecules have biological effects opposite to those of inhibins in the regulation of FSH and also play a paracrine role in follicular growth.

Subunit synthesis occurs in granulosa cells through the translation of protein precursors that undergo proteolytic cleavage and maturation processes in the endoplasmic reticulum and Golgi apparatus. After secretion, the mature molecules can act locally within the follicular microenvironment or enter the systemic circulation and exert endocrine effects on the pituitary.

The biological activity of activins is further modulated by binding proteins such as follistatin, which can neutralize the ligand and limit its action. This modulatory system allows precise regulation of the signal and prevents excessive stimulation of follicular growth.

The primary endocrine function of inhibins is the modulation of pituitary FSH secretion. When antral follicles begin to develop, granulosa cells produce inhibin B, which enters the systemic circulation and reaches the anterior pituitary. There, the molecule acts on gonadotroph cells by reducing FSH synthesis and secretion.

This mechanism constitutes one of the main systems of negative ovarian feedback. Increased inhibin production signals the presence of growing follicles to the pituitary and limits the rise in FSH, preventing the simultaneous recruitment of numerous follicles. In this way, the body promotes the progressive selection of a single dominant follicle.

During the luteal phase, inhibin A secretion further contributes to the suppression of FSH. At the end of the cycle, regression of the corpus luteum causes inhibin levels to decrease, allowing a new rise in FSH that initiates follicular growth for the subsequent cycle.

The circulating concentration of inhibin B therefore reflects antral follicle activity and represents an indicator of ovarian function. In clinical practice, measurement of this peptide has been used as a marker of follicular reserve and as a biological marker in certain ovarian neoplasms derived from granulosa cells.

Activins exert effects opposite to those of inhibins in the regulation of the hypothalamic-pituitary-gonadal axis. These molecules stimulate synthesis of the FSH β subunit in pituitary gonadotroph cells and promote hormone secretion. Their biological action is mediated by membrane receptors belonging to the TGF-β family, which activate intracellular signaling pathways dependent on SMAD proteins.

In addition to their endocrine action on the pituitary, activins play a paracrine role in the regulation of folliculogenesis. In granulosa cells, they stimulate cellular proliferation, differentiation and increased expression of FSH receptors. This amplification of follicular sensitivity to the gonadotropin promotes the progression of follicles toward more advanced stages of development.

Activin activity is regulated by several modulatory proteins, including follistatin and accessory receptors such as betaglycan, which modulate its biological availability. The balance between activin and inhibin therefore determines the effective level of FSH stimulation and contributes to the regulation of follicular growth.

This system demonstrates that regulation of the reproductive axis depends not only on pituitary gonadotropin secretion, but also on ovarian signals that directly modulate both the pituitary response and follicular sensitivity to endocrine stimulation.

AMH is a glycoprotein belonging to the TGF-β family and produced by the granulosa cells of preantral and early antral follicles. In the adult ovary, its physiological role is to control the rate at which primordial follicles enter the growing pool and to modulate follicular sensitivity to gonadotropins.

The main biological effect of AMH is the limitation of follicular recruitment. The hormone reduces the likelihood that primordial follicles will be activated and slows their transition toward subsequent stages of growth. This mechanism contributes to preserving the follicular population over time and preventing excessively rapid depletion of ovarian reserve.

In follicles that have already entered the growth process, AMH reduces the sensitivity of granulosa cells to FSH, thereby modulating progression toward the antral stage. In this way, it acts as a local regulator of folliculogenesis and helps maintain the balance between follicular recruitment and selection.

From a clinical perspective, the serum concentration of AMH reflects the number of antral follicles present in the ovary and represents one of the most widely used indicators of ovarian reserve. Hormone levels progressively decline with age and become very low when the follicular population decreases, as occurs during the menopausal transition.

Elevated AMH values may be observed in conditions characterized by an increased number of antral follicles, such as polycystic ovary syndrome. In clinical practice, AMH measurement is used to assess ovarian function, predict the response to ovarian stimulation and investigate certain infertility conditions.

The physiology of inhibin, activin and AMH demonstrates that ovarian function is regulated by a complex network of endocrine and paracrine signals. The ovary is not merely an effector organ of gonadotropins, but also a regulatory center that sends feedback signals to the pituitary and modulates its own follicular dynamics through local factors.

Inhibins convey information about the presence of growing follicles to the pituitary and reduce FSH secretion when follicular activity is high. Activins exert the opposite effect and amplify the follicular response to the gonadotropin. AMH instead regulates the rate at which primordial follicles enter the growth process, thereby contributing to the preservation of ovarian reserve.

The interpretation of biomarkers derived from these systems nevertheless requires caution. Circulating levels of inhibin or AMH reflect the status of the follicular population, but do not provide a complete description of oocyte quality or individual reproductive capacity. In addition, factors such as age, endocrine conditions and ovarian disorders may alter the production of these peptides without necessarily carrying the same biological significance.

In summary, inhibin, activin and AMH are fundamental components of ovarian physiology. Through a system of endocrine feedback and intraovarian paracrine regulation, these molecules coordinate the pace of folliculogenesis, modulate gonadotropin secretion and contribute to the preservation of reproductive function over time.