Version May 2024
INTRODUCTION — Control of the reproductive axis originates in the hypothalamus with the periodic pulsatile release of gonadotropin-releasing hormone (GnRH). In response to GnRH (also called luteinizing hormone-releasing hormone or LHRH), the pituitary releases pulses of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), into the blood stream. These hormones then induce gonadal production of a variety of hormones such as estradiol, progesterone, inhibins, and testosterone that play an important role in the regulation of reproduction.
RELEASE OF GNRH — Several elements are necessary for the normal release of and response to GnRH; migration of the secretory neurons via the proper route to the proper location must take place in the developing embryo, and secretion must occur in a pulsatile fashion in response to neuroendocrine inputs and sex steroids.
Embryonic migration — GnRH is released from a small number of hypothalamic neurons that appear to arise in the developing embryo from an epithelial cluster of cells in the olfactory placode outside the central nervous system, although evidence in zebrafish suggest the neurons arise from the anterior pituitary placode and cranial neural crest, then transiently associate with the olfactory placode [1-3]. Regardless of their site of origin, fetal cells in the olfactory area can respond to odorant stimuli and secrete GnRH [4]. These neurons then migrate into the olfactory bulb and olfactory tract before continuing to move into the mediobasal hypothalamus in the preoptic area and the arcuate nucleus.
Migration is an essential feature of developing GnRH neurons, as demonstrated by studies in which the GnRH neurons in fetal hypothalamic tissue were transplanted to the floor of the third ventricle in GnRH-deficient (hpg) mice. The GnRH neurons migrated to the correct hypothalamic location and sent projections to the median eminence [5].
The critical role of migration has been confirmed in humans in a study of an aborted human fetus with Kallmann syndrome [6]. The fetus had the same X chromosome deletion as its living GnRH-deficient brother. Neuropathological examination showed arrest of the GnRH neurons at the cribriform plate of the ethmoid sinus at a time when the GnRH neurons in a normal fetus would have already migrated to the hypothalamus. These observations facilitated the discovery that anosmin-1, the protein encoded by the KAL1 gene responsible for X-linked Kallmann syndrome, plays a role in GnRH neuronal migration [7]. The fibroblast growth factor receptor 1 (FGFR1) also plays a role in GnRH neuronal migration, and mutations in FGFR1 and its ligand FGF8 are associated with Kallmann syndrome [8-10]. The association of GnRH neurons with the olfactory bulb and tract is thought to explain the high frequency of anosmia (lack of smell) in patients with GnRH deficiency [11,12]. Other gene mutations resulting in GnRH deficiency are reviewed in detail separately. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)".)
Pulsatile GnRH secretion — For proper stimulation of gonadotropin release, GnRH neurons must be properly located and must secrete in a pulsatile fashion (waveform 1). Some GnRH neuron axons terminate on cell bodies of other GnRH neurons, suggesting a mechanism for coordinate control of pulsatility [13]. In addition, immortalized GnRH neurons in vitro continue to release GnRH in a pulsatile fashion, suggesting the existence of an intrinsic hypothalamic pulse generator [14].
Appropriate pulsatile release of GnRH stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In turn, the pattern of LH and FSH release induces gonadal production of steroid hormones, including the steroids estradiol, progesterone, testosterone, and androstenedione, and other factors, such as the protein hormones inhibin and activin.
The control of GnRH release is complex. There appears to be a pulse generator that coordinates the secretion of GnRH in discrete, random, but regular bursts. Multiple neurotransmitters and neurohormones have been implicated as having a role in the control of GnRH secretion, including catecholamines, opiates, neuropeptide Y, galanin, corticotropin-releasing hormone, kisspeptin, neurokinin B, dynorphin, and prolactin, as well as gonadal steroids.
Sex steroids have both positive and negative feedback effects on GnRH pulse frequency. How this occurs is not well understood. Sex steroid receptors have been difficult to identify in hypothalamic GnRH-secreting neurons [15,16] and their existence remains controversial. However, estrogen receptors have been found in adjacent cells in the hypothalamus. Glial cells have steroid hormone receptors and are likely to be intimately involved in transmitting sex steroid feedback (and other signals) to GnRH neurons [17].
The GPR54 gene, which encodes the G-protein coupled kisspeptin receptor, appears to be important for normal hypothalamic GnRH processing or secretion. Mutations in this gene and its ligand kisspeptin have been reported in some patients with congenital GnRH deficiency without anosmia (idiopathic hypogonadotropic hypogonadism [IHH]). Mutations in neurokinin B and its receptor have also been reported in patients with congenital IHH and may work through kisspeptin [18]. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)".)
Pulsatile gonadotropin response — The frequency and amplitude of LH pulses is a crucial component of normal reproductive development and maintenance. On the other hand, disruption of the normal pattern of pulsations is associated with multiple disorders of human reproduction. Thus, understanding the pathophysiology of reproductive disorders requires some assessment of the pulsatility of GnRH secretion. Since the hypothalamus and the portal blood supply are not safely accessible in the human, direct sampling of GnRH is not possible. In addition, measurements of GnRH in the peripheral circulation do not accurately reflect its secretion due to its rapid half-life of two to four minutes [19]. Therefore, serum LH is used as a surrogate marker of hypothalamic GnRH secretion.
Each pulse of LH measured in the peripheral blood corresponds to a hypothalamic pulse of GnRH into the portal system in a one-to-one relationship (waveform 1) [20]. As an example, GnRH-deficient individuals have no pulses of LH detected in their peripheral blood; they will, however, respond to exogenous GnRH with a pulse of LH for each pulse of GnRH given [21]. Prolonged administration of pulses of GnRH in these patients can lead to normal pubertal development and the ability to conceive. Although FSH is released with LH, FSH pulses are much more difficult to detect because the half-life of FSH is longer than the interval between GnRH pulses.
The requirement for stimulation of the pituitary gonadotrophs to secrete FSH and LH by pulses of GnRH has been documented by frequent blood sampling in many experimental models [22,23] and by the administration of GnRH to GnRH-deficient humans [21]. The response is different if GnRH is administered continuously. With continuous administration, serum gonadotropin concentrations temporarily increase (the agonist effect) and then decrease in response to desensitization (figure 1) [21,23,24]. The development of desensitization has become important clinically as long-acting GnRH agonists (such as leuprolide, nafarelin, or goserelin) are being used to suppress gonadotropin and therefore sex steroid release in a variety of conditions including precocious puberty, prostate cancer, breast cancer, uterine fibroids, and endometriosis [25-29]. When the agonist is withdrawn, spontaneous GnRH pulses resume, leading to restoration of gonadotropin pulsations and gonadal responses.
PHYSIOLOGIC FUNCTIONS — The pattern of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) pulses appears to regulate a variety of important functions including the onset of human sexual differentiation and puberty, as well as adult sex steroid production and fertility.
●In females, FSH promotes follicular development, whereas LH is critical for ovulation, stimulation of androgens (the estradiol precursors) from theca cells, and maintenance of the corpus luteum. (See "Normal menstrual cycle".)
●In males, LH is generally responsible for stimulating testosterone production from the Leydig cells in the testes. FSH, in concert with high intratesticular testosterone levels, is required for spermatogenesis.
The ensuing release of gonadal hormones then has modulating effects on both hypothalamic and pituitary function:
●Estradiol, progesterone, and testosterone feedback negatively to reduce the release of LH and FSH; these effects appear to occur at both pituitary and hypothalamic sites of action.
●Inhibin suppresses FSH more than LH synthesis and secretion, while activin stimulates FSH release.
One can therefore use the combination of serum gonadotropin and sex steroid values to determine if a defect in reproductive function is due to an abnormality of the gonads or to an abnormality in the hypothalamic or pituitary release of gonadotropins.
Serum sex steroid concentrations will be low in patients with both disorders, but serum gonadotropin concentrations will be high in patients with gonadal dysfunction (due to loss of negative feedback) and low or normal in those with hypothalamic or pituitary disease.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Infertility treatment with gonadotropins (Beyond the Basics)")
SUMMARY — Control of the reproductive axis originates in the hypothalamus with the periodic pulsatile release of gonadotropin-releasing hormone (GnRH). In response to GnRH, the pituitary releases pulses of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), into the blood stream. These hormones then induce gonadal production of a variety of hormones, such as estradiol, progesterone, inhibins, and testosterone, that play an important role in the regulation of reproduction.
The following elements are necessary for the normal hypothalamic secretion of and pituitary response to GnRH:
●GnRH neurons must be properly located; migration of the secretory GnRH neurons takes place in the developing embryo. These neurons then migrate into the olfactory bulb and olfactory tract before continuing to move into the mediobasal hypothalamus in the preoptic area and the arcuate nucleus. (See 'Embryonic migration' above.)
●GnRH secretion must occur in a pulsatile fashion in response to neuroendocrine inputs and sex steroids. There appears to be a pulse generator that coordinates the secretion of GnRH in discrete, random, but regular, bursts. (See 'Pulsatile GnRH secretion' above.)
●The pituitary has an absolute requirement that GnRH secretion be pulsatile in order to secrete LH and FSH (waveform 1). Continuous, rather than pulsatile, administration of GnRH results in pituitary desensitization (figure 1). This observation is the basis for the clinical use of GnRH agonists, which are used to suppress gonadotropin secretion and therefore gonadal steroids in a variety of conditions including precocious puberty, prostate cancer, breast cancer, uterine fibroids, and endometriosis. (See 'Pulsatile gonadotropin response' above.)
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