Index
It is an essential decapeptide for mammalian reproduction.
As a hormone, it stimulates the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
Function
Gonadotropin-releasing hormone (GnRN) is released as a neurohormone from the median eminence to the pituitary portal system.
Normal reproductive function requires precise temporal and quantitative regulation of hormone secretion at all levels of the hypothalamic- pituitary-gonadal axis.
The hypothalamus contains neurons that release gonadotropin (GnRH) and secrete pulsatile GnRH into the pituitary portal blood system through which it is transported to the anterior pituitary gland.
GnRH binds to its receptor on gonadotropic cells, stimulating the biosynthesis and secretion of gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH).
LH and FSH travel through the peripheral circulation, acting on the gonads to stimulate gametogenesis (that is, the development of mature eggs and sperm) and steroidogenesis (that is, synthesis of the gonadal hormones – estrogen, progesterone, and androgens).
In most physiologic conditions, gonadal steroids feed back into the hypothalamus and pituitary gland to decrease GnRH and gonadotropin secretion.
An exception is at the time of periovulatory LH surge in women, which is believed to be due to positive feedback from rapidly rising estradiol levels.
Isolated in the early 1970s, GnRH was one of the first hypothalamic-releasing hormones to be sequenced and characterized.
Initially, separate hypothalamic factors were believed to be responsible for the secretion of LH and FSH, and as a result, GnRH was originally called luteinizing hormone-releasing factor (LHRH).
Like other neuropeptides, GnRH is synthesized as part of a large prohormone that is enzymatically cleaved and further modified within secretory granules.
This 92 amino acid precursor protein is proteolytically cleaved to generate:
- The GnRH decapeptide.
- A 23 amino acid signal sequence that directs intracellular packaging and secretion.
- A three amino acid proteolytic (Gly-Lys-Arg) processing site.
- A 56 amino acid GnRH associated protein (GAP) that is secreted with GnRH. The function of GAP is unknown, but it has been proposed to inhibit prolactin secretion in some species.
GnRH has a short half-life of approximately 2-4 minutes due to rapid cleavage by peptidases.
As a result of this rapid degradation and massive dilution, the peripheral circulation does not contain biologically active concentrations of GnRH.
Serum LH and FSH levels are used clinically as surrogate markers for the presence of pulsatile GnRH secretion. LH is a more accurate indicator of GnRH pulse characteristics (ie frequency and amplitude) than FSH which has a longer half-life.
Most of our understanding of GnRH and GnRH receptor (GnRHR) function is based on studies of a single isoform of each; however, recent studies have identified additional forms as described in later sections.
For this review, the terms “GnRH” and “GnRHR” will refer to the type GnRH and GnRHR, respectively. Also note that Human Gonadotropin Releasing Hormone must be abbreviated in all capital letters (i.e. GNRH) according to the new nomenclature.
As much of the available data has been obtained in non-human species, we have chosen to use the most common abbreviations.
GnRH migration during development
While most neuronal cells arise from neurons within the developing nervous system itself, GnRH neurons are unusual in that they are derived from progenitor cells in the epithelium of the olfactory placode.
These nascent GnRH neurons migrate along the vomeronasal axons, through the cribriform plate, and into the midbasal hypothalamus where migration ceases and the neurons detach from their axonal guides.
Patients with delayed puberty due to abnormal GnRH neuronal migration often have associated anosmia, or the inability to smell, reflecting the fact that GnRH neurons share common embryonic origins and migration paths with olfactory neurons.
Identifying genes that drive normal GnRH migration and function is an active area of research. A long list of soluble factors has been identified that appear to be critical to the eventual development of a network containing the appropriate number and location of GnRH neurons.
These include pathway markers (netrin-1), cell cycle arrest (Gas6), signaling molecules (GABA), growth factors (fibroblast growth factors), and adhesion molecules (tenascin, phosphacan, and laminin).
Mutations in these genes result in clinical phenotypes that include delayed puberty and infertility.
Estimates of the number of GnRH neurons vary, but are in the range of a few thousand, a remarkably small number in view of their critical function.
The cell bodies of these neurons are scattered through various hypothalamic nuclei, with the majority residing in the arcuate nucleus of the medial basal hypothalamus in humans.
Most GnRH neurons send axonal projections to the median eminence that borders the hypothalamic-pituitary portal system.
This system consists of capillaries that arise from the superior pituitary arteries, traverse the pituitary stalk, and then form a capillary network within the pituitary gland. This anatomical relationship allows small amounts of GnRH secreted by these axonal terminals to have direct access to the prostatic gonads.
The primary direction of this pituitary portal system is from the hypothalamus to the pituitary; however, retrograde flow also exists and provides a short feedback loop from the pituitary to the hypothalamus.
A subset of GnRH neurons extend axons to other parts of the CNS, including the limbic system. While these projections are not directly involved in modulating gonadotropin secretion, they can help link hormonal status with reproductive behavior.
Thus, GnRH neurons are positioned to receive and generate neural and hormonal inputs, allowing complex integration of reproductive function and a broader physiological state.
Hypothalamus secretion
Pulsatile GnRH is required to achieve sustained gonadotropin secretion. Using a primate model, continuous infusion of GnRH was found to rapidly suppress both LH and FSH secretion, an effect that was easily reversed with a return to pulsatile stimulation.
It is now known that the loss of the GnRH response with continuous treatment is due to rapid uncoupling of the GnRH receptor from its intracellular signaling molecules followed by down-regulation of the number of receptors.
This feature is exploited clinically by the administration of long-acting GnRH agonists to treat steroid-dependent conditions, such as endometriosis, leiomyomas, breast cancer, and prostate cancer.
Pulsatile activity is currently believed to be an intrinsic property of GnRH neurons with hormonal and neuronal inputs that provide modulating effects.
However, it has never been definitively proven whether the pulse generator is within a single GnRH neuron or a property of the neural network.
GnRH neuronal activity throughout life
The neuronal activity of GnRH varies throughout life, as reflected by changes in gonadotropin levels and, ultimately, the production of gonadal steroids and gametes.
In humans, GnRH is detectable in the hypothalamus at 10 weeks gestational age with FSH and LH produced for 10-13 weeks when the vascular connection between the hypothalamus and the pituitary gland has developed.
Gonadotropin levels peak in mid-gestation and then decline towards term due to negative feedback in both the hypothalamus and pituitary gland from high levels of placental steroids.
With the withdrawal of placental steroids at birth, gonadotropins increase and remain elevated for the first 1-2 years in girls and the first 6 months in boys with a subsequent decrease during the remainder of childhood.
At puberty, pulsatile gonadotropin secretion resumes, first at a low frequency during the night and finally achieving the normal adult reproductive pattern.
In adult men, gonadotropin pulses, and presumably GnRH pulses, occur approximately every 2 hours. In women, the characteristics of the GnRH pulse vary depending on the time of the menstrual cycle with pulses of more frequent amplitude but less amplitude during the follicular phase.
High-frequency pulses of approximately every 60-90 minutes favor LH secretion in the follicular phase, while low-frequency pulses every 200 minutes favor FSH secretion in the late luteal phase.
High levels of progesterone and proportionally lower levels of estrogen during the luteal phase may contribute to the preferential release of FSH at this time.
This increase in FSH is critical for the initiation of follicular recruitment during the early follicular phase of the following cycle. Relatively recent data strongly suggest that kisspeptin neurons are responsible for the activation of the hypothalamic-pituitary-gonadal axis at puberty.
GnRH pulse characteristics change once more at menopause. There is a long-standing consensus that women are born with the full cohort of follicles that they will have in their lifetime.
With depletion of follicular number, estrogen levels decline with subsequent loss of negative feedback and resulting increases in GnRH secretion.
GnRH pulses occur approximately every 50-55 minutes in younger postmenopausal women, which is comparable to a woman who normally cycles in the late follicular phase and at the peak of the mid cycle.
As women age between the 5th and 8th decade, the frequency of the GnRH pulses decreases by approximately 35%. Of interest, data are emerging suggesting that stem cells may exist in the ovary; however, this is currently a controversial area of research.
Hormonal regulation of GnRH secretion
Estradiol is likely to act in both the hypothalamus and the pituitary gland to exert negative and positive feedback effects on GnRH secretion and gonadotropin release.
Within the hypothalamus, altered GnRH pulsatility can be the result of direct or indirect effects on GnRH neurons.
For many years, it was believed that GnRH neurons lacked estrogen receptor expression, suggesting that all effects on these neurons were achieved through interneuron connection.
However, more recent studies have shown that the estrogen receptor, ERb, is expressed by at least a subset of GnRH neurons.
The presence of ERa is more controversial, although ERa mRNA has been clearly identified in some studies.
Some of these discrepancies may be attributable to species differences. There is also substantial evidence to support a direct negative effect of estrogens at the pituitary level.
For example, studies have been conducted in GnRH-deficient women who were treated with pulsatile GnRH followed by estradiol. Estradiol was able to mitigate GnRH-mediated increases in gonadotropin expression, despite the lack of potential feedback in the hypothalamus.
Circulating estradiol levels are a reflection of the degree of ovarian follicular development.
Although low estradiol levels provide negative feedback as just described, rapidly rising estradiol levels exert a positive feedback effect and are responsible for generating the preovulatory gonadotropin surge.
Estradiol levels of 200-400 pg / ml that persist for at least 36 hours have been shown in a monkey model to be adequate to generate an LH surge.
In the normal physiological situation, estradiol probably acts through both the hypothalamus and the pituitary gland to trigger the LH surge.
Within the pituitary, estradiol and GnRH increase GnRHR expression, increasing the sensitivity of the pituitary to GnRH pulses.
Hypothalamic GnRH secretion is also increased at the time of increase, measured directly in sheep and rats; However, this change may not be required.
It is possible to generate an estradiol-induced surge experimentally despite keeping the GnRH pulse rate and amplitude constant in animals lacking endogenous GnRH activity.
Therefore, although GnRH release normally increases at the time of augmentation, this increase appears to be easier than essential for the production of a surge.
Progesterone also decreases GnRH secretion at the level of the hypothalamus. It is controversial whether GnRH neurons express progesterone receptors and therefore interneurons expressing these receptors may be responsible for the feedback effects.
It has been clearly established that estrogen preparation is necessary to observe a progestational effect, undoubtedly due to the marked ability of estrogen to positively regulate progesterone receptor expression.
Several neurotransmitters and neuropeptides are believed to act as intermediaries between the circulating levels of gonadal steroids and the pulse secretion of GnRH. For example, estrogen promotes endorphin secretion with a further increase in the presence of progesterone.
Endorphins, along with other opioids, suppress the hypothalamic release of GnRH.
Therefore, endorphin levels peak with the high levels of steroids found in the mid-luteal phase, suggesting that opioid tone may act with progesterone to decrease the GnRH pulse rate in this phase relative to the follicular phase.
Neurons that secrete NPY, norepinephrine, and dopamine are also likely to be important for modulating neuronal GnRH activity.
Furthermore, CRH has been shown to inhibit hypothalamic GnRH secretion, both directly and by increasing endogenous opioid secretion.
