A number of hormones and hormone-like substances are involved in regulating the reproductive process in humans. Some are well studied, others less so. It is not our aim to discuss all of them. In this post we will restrict our discussion to those hormones whose structure and function have been well studied and are universally accepted.
Luteinizing Hormone-Releasing Hormone
The neurohormone involved in regulating the synthesis and release of both folliclestimulating hormone and luteinizing hormone is gonadotropin-releasing hormone, also known as luteinizing hormone-releasing hormone. It is a decapeptide secreted from the luteinizing hormone-releasing hormone neurons of the hypothalamus into the portal vessels. Luteinizing hormone-releasing hormone modulates both luteinizing hormone and follicle-stimulating hormone, neither of them selectively. The half-life of luteinizing hormone-releasing hormone is 2-4 min. It is secreted as a pulse every hour during the follicular phase and every 3 h during the luteal phase. Its main function is to promote synthesis, storage and release of gonadotropins. Pulsatile secretion of luteinizing hormone-releasing hormone leads to pulsatile release of luteinizing hormone and follicle-stimulating hormone. Therefore, hypothalamic luteinizing hormone-releasing hormone neurons regulate the synthesis and secretion of follicle-stimulating hormone and luteinizing hormone by the anterior pituitary. Alteration of the output of follicle-stimulating hormone and luteinizing hormone can be achieved by increasing or decreasing the amplitude or frequency of luteinizing hormone-releasing hormone pulses.
Follicle-Stimulating Hormone and Luteinizing Hormone
Follicle-stimulating hormone and luteinizing hormone are responsible primarily for the processes concerned with follicular and germ cell development and with ovulation. Luteinizing hormone and follicle-stimulating hormone are secreted by the gonadotrophic cells (basophilic), which comprise about 10% of the anterior pituitary. Luteinizing hormone and follicle-stimulating hormone are heterodimeric glycoprotein hormones of similar size, and consist of a common a chain and a distinct в chain. The same a chain is present in thyroid-stimulating hormone and human chorionic gonadotropin. The a subunit is encoded by a single gene located on chromosome 6, while the follicle-stimulating hormone в subunit is located on chromosome 11 and the luteinizing hormone в subunit on chromosome 19. follicle-stimulating hormone has a longer half-life than luteinizing hormone (Table Properties of human luteinizing hormone, luteinizing hormone-releasing hormone, follicle-stimulating hormone and prolactin). Secretion of luteinizing hormone and follicle-stimulating hormone is under the control of luteinizing hormone-releasing hormone, which, as mentioned above, is secreted in a pulsatile fashion. Luteinizing hormone is released in pulses at a frequency of every 60-90 min during the follicular phase and every 3 h during the luteal phase. The mechanism of follicle-stimulating hormone and luteinizing hormone action involves binding to specific cell membrane receptors and subsequent activation of the adenylate cyclase system, which in turn leads to signaling steps within the cell.
Follicle-stimulating hormone receptors are present only on granulosa cells. Follicle-stimulating hormone stimulates the growth and division of the granulosa cells of the ovarian follicle and controls the aromatase responsible for estradiol formation within these cells. It also induces the synthesis of luteinizing hormone receptors on the granulosa cells and is involved in the production of inhibin, activin and insulin-like growth factor I. luteinizing hormone stimulates the ovarian theca cells to produce androgens, which diffuse to the granulosa cells where they are converted into estrogens. Plasma estradiol peaks before the luteinizing hormone surge, which in turn, triggers ovulation. Postovulation luteinizing hormone contributes to the formation of the corpus luteum. Once conception has occurred, pituitary gonadotropins are no longer required to sustain the pregnancy.
Estradiol, Progesterone and Feedback Control of Follicle-Stimulating Hormone and Luteinizing Hormone Secretion
The plasma concentrations of circulating follicle-stimulating hormone and luteinizing hormone increase markedly after the menopause or after surgical castration. This rise is attributable to the decline of estradiol and inhibin (mainly inhibin B) secretion. Administration of physiologic doses of estradiol mimicking those found in the follicular phase of the menstrual cycle in reproductive aged women leads to a decline of follicle-stimulating hormone and luteinizing hormone to levels approximately 50% of the postmenopausal level. This is an example of classic negative feedback in premenopausal women. It requires a relatively small rise from low circulating levels of estradiol for an effect on follicle-stimulating hormone and luteinizing hormone to be observed. Furthermore, the effect of estradiol is seen very quickly. However, because inhibin is not administered in hormone replacement therapy the postmenopausal follicle-stimulating hormone and luteinizing hormone values do not return to within the premenopausal range with hormone replacement therapy. In regularly menstruating women, if plasma concentration of estradiol increases two- to four-fold and this increase is sustained over 48 h or so, then luteinizing hormone and follicle-stimulating hormone secretion is enhanced, not suppressed. This is termed positive feedback. The most important effect of progesterone is that high plasma levels of this hormone enhance the negative feedback of estradiol and suppress follicle-stimulating hormone and luteinizing hormone secretion to a very low level. By contrast, low levels may enhance the positive feedback of estradiol.
The hormone prolactin is produced by the lactotrophic cells (acidophilic) of the anterior pituitary. It constitutes 15-20% of the normal pituitary and this increases to 70% during pregnancy. Prolactin has a single polypeptide chain containing 198 amino acids. The gene for prolactin production is on chromosome 6. The hormone is essential for lactation and a mass of the receptors for this hormone is present in the human breast and gonads. It may also have some function in the regulation of steroidogenesis in the ovary. The plasma levels vary during the day, the highest plasma concentration occurring during sleep. Under normal circumstances, prolactin secretion is restrained by the hypothalamus and the inhibitory factor for prolactin appears to be dopamine. Prolactin release is stimulated by sleep, estrogen, suckling, stimulation of the nipple, thyrotropin-releasing hormone, stress, opiates and anti-dopamine medications. Some of the properties of luteinizing hormone-releasing hormone, luteinizing hormone, follicle-stimulating hormone and prolactin are summarized in Table Properties of human luteinizing hormone, luteinizing hormone-releasing hormone, follicle-stimulating hormone and prolactin.
Inhibins, Actwins and Follistatinis
Inhibins, activins and follistatins are produced by the ovary and are a part of a larger family of growth factors. Inhibins are proteins that consist of a common a subunit and one of two в subunits (вA or вB). They are classified as inhibin A if they contain вA chain or inhibin B if they contain вB chain. Activins are proteins that have two в chains (homodimers — pA/pA, вB/pB; or heterodimers — вA/pB) butno a chains.
Inhibin A is mainly produced by the dominant follicle and the subsequent corpus luteum. It is maintained at relatively constant low levels through most of the follicular phase, then exhibits a late follicular phase rise (in keeping with its production by the dominant follicle), a midcycle peak, and a long peak with the highest levels recorded during the luteal phase. Inhibin A appears to exert negative feedback on follicle-stimulating hormone during the luteal phase of the cycle.
Inhibin B is found in the granulosa cells of antral follicles during the end of the luteal phase of the preceding cycle and the early follicular phase of the next; its concentration in plasma changes in parallel with follicle-stimulating hormone: it rises in the early follicular phase, declines toward midcycle, shows a midcycle peak and reaches its lowest level during the luteal phase. This suggests it is produced by the cohort of small antral follicles and suppresses follicle-stimulating hormone in the follicular phase. Inhibin B is currently being evaluated as a test for ovarian reserve (the ability of the ovary to produce oocyte(s) in response to stimulation with fertility drugs).
Inhibin A, together with a-fetoprotein and free proteins-human chorionic gonadotropin, shows much promise in serologic testing for Down’s syndrome in early pregnancy. Activins and follistatins are less well studied. As the names suggest, one property of the activins is to enhance the secretion of follicle-stimulating hormone, while follistatins suppress it by binding and inactivating the activins. Their role as gonadal feedback regulators is still under investigation.