Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Oxford Academic. Google Scholar. Select Format Select format. Permissions Icon Permissions. Issue Section:. You do not currently have access to this article. Download all slides. Sign in Don't already have an Oxford Academic account? Administration of FSH to humans and animals induces "superovulation", or development of more than the usual number of mature follicles and hence, an increased number of mature gametes.
FSH is also critical for sperm production. It supports the function of Sertoli cells, which in turn support many aspects of sperm cell maturation.
GnRH is a ten amino acid peptide that is synthesized and secreted from hypothalamic neurons and binds to receptors on gonadotrophs. As depicted in the figure to the right, GnRH stimultes secretion of LH, which in turn stimulates gonadal secretion of the sex steroids testosterone, estrogen and progesterone.
In a classical negative feedback loop , sex steroids inhibit secretion of GnRH and also appear to have direct negative effects on gonadotrophs. In females, pulse frequency is clearly related to stage of the cycle.
Numerous hormones influence GnRH secretion, and positive and negative control over GnRH and gonadotropin secretion is actually considerably more complex than depicted in the figure.
For example, the gonads secrete at least two additional hormones - inhibin and activin - which selectively inhibit and activate FSH secretion from the pituitary. This condition is typically manifest in males as failure in production of normal numbers of sperm. In females, cessation of reproductive cycles is commonly observed.
Elevated blood levels of gonadotropins usually reflect lack of steroid negative feedback. Removal of the gonads from either males or females, as is commonly done to animals, leads to persistent elevation in LH and FSH. Thus, endorphin levels peak with the high steroid levels found in the mid-luteal phase, suggesting that opioid tone may act with progesterone to decrease GnRH pulse frequency in this phase relative to the follicular phase. NPY, norepinephrine and dopamine-secreting neurons are also likely to be important for modulation of GnRH neuronal activity.
In addition, it has been demonstrated that CRH inhibits hypothalamic GnRH secretion, both directly and by augmenting endogenous opioid secretion. Women with hypothalamic amenorrhea and women under high levels of stress experience hypercortisolism, suggesting that this may be at least one pathway by which these pathophysiologic states interrupt reproductive function.
The discovery of the kisspeptin neuronal system has substantially advanced our understanding of the regulation of the hypothalamic GnRH system at puberty, across the female reproductive cycle, and at menopause. The majority of the kisspeptin studies have been performed in rodents, but at least fundamental similarities are being documented in primate models.
Humans with mutations in the kisspeptin receptor experience hypogonadotropic hypogonadism, strongly suggesting a key role in GnRH neuronal function in humans. Kisspeptin is a amino acid polypeptide which binds to a specific receptor, termed the G protein-coupled receptor 54 GPR Kisspeptin secreting neurons are located in the arcuate and anteroventral periventricular AVPV nuclei of the hypothalamus. The majority of kisspeptin neuronal mapping has been done in rodents, but the presence of kisspeptin secreting neurons in the arcuate nucleus has been established in humans.
Kisspeptin neurons may act directly or transsynaptically by way of neuorotransmitters. Arcuate kisspeptin neurons are not as abundant as AVPV neurons, but are in much closer proximity to GnRH neurons in the median eminence. The onset of puberty is marked by an increase in synaptic connections between Kiss1 and GnRH neurons.
Evidence also suggests an overall elevation in kisspeptin tone as well as enhanced kisspeptin signaling efficacy. These changes appear to occur primarily via the AVPV neurons and, in the female, may be triggered by subtle increases in ovarian estrogen production. Expression of the KISS1 gene is under the control of both estrogens and androgens. Sexual dimorphism also exists in that estrogen is unable to generate a surge in the male, possibly due to the greater number of kisspeptin neurons in the AVPV of adult females compared to males.
Kisspeptin expression is further modified by the adipose-derived factor, leptin. A amino acid polypeptide, leptin is secreted by white adipose tissue and regulates body weight by decreasing food intake and increasing energy expenditure. Within the arcuate nucleus, leptin has been shown to increase activity of the kisspeptin neurons. A third form of GnRH, GnRH3, has been reported in several fish species but is not currently thought to be present in humans.
In the human, the gene encoding GnRH1 is found on chromosome 8p11, whereas the gene for GnRH2 is found on chromosome 20p The genes for both forms of GnRH are composed of four exons and three introns which encode an identically organized precursor polypeptide.
Expression of the GnRH1 and GnRH2 genes are driven by different promoter sequences, suggesting that their transcriptional regulation likely differs. Detailed analysis of the GnRH1 gene promoter sequence has identified a number of DNA-regulatory regions which provide for tissue-specific expression.
GnRH1 and GnRH2 are expressed in overlapping tissue patterns; however, as a general rule, GnRH2 can be detected in a broader range of tissues and is present at higher levels outside of the brain. The presence of GnRH1 in human thyrotropes and somatotropes, suggests additional roles for GnRH signaling in the pituitary.
GnRH1 and GnRH2 have been found in reproductive tissues including the ovary, prostate, endometrium, breast and placenta as well as in tumors derived from these tissues. In the central nervous system, both isoforms have been localized to the preoptic and mediobasal regions with additional GnRH2 expression in midbrain regions such as the hippocampus, caudate nucleus, and amygdala.
Furthermore, in these same cells, treatment with the progesterone antagonist RU increases GnRH2 transcript number but does not alter GnRH1 expression. The gene which encodes the GnRHR is located on chromosome 4 in the human. While additional GnRHR isoforms have been identified in other species, at present, only a single GnRHR peptide has been definitively detected in humans. Although the mRNA for a putative type 2 receptor has been detected in endometrium, ovary, testes, placenta, and prostate cells, this transcript contains a frame-shift that generates a premature stop codon and lacks a methionine translation initiation codon.
As such, it is unlikely that this receptor is expressed in a functional form. Nevertheless, it has been proposed that the truncated human GnRHR2 may play a modulatory role in GnRHR1 expression by perturbing normal processing of the latter. As previously described, GnRH is expressed in a wide range of non-pituitary tissues.
Likewise, GnRH receptors have been identified in an extensive array of normal tissues, as well as benign and malignant tumors derived from these tissues. GnRHR expression has been detected in reproductive tissues including the ovary, testes, endometrium, myometrium, prostate, breast and placenta.
Within reproductive tissues, GnRH and its receptor are thought to play a role in normal breast and ovarian development. In the adult ovary, the expression of GnRHR correlates with stage of follicular growth, with high levels of GnRHR binding in granulosa cells from late follicles and developing corpora luteal cells, but limited binding in primordial, early antral, and preovulatory follicles.
This stage-specific timing suggests significant effects on cellular proliferation, differentiation, and steroidogenesis. In non-reproductive tissues, GnRH has been reported to modulate neuronal migration, visual processing, digestive tract function, and immune T cell chemotaxis.
Studies in endometrial, ovarian, and prostate tumor cell lines have implicated GnRH in mediating cell growth, angiogenesis, invasion, and metastasis. The GnRH receptor GnRHR is a member of the rhodopsin-like G protein-coupled receptor superfamily characterized by the presence of a hydrophilic extracellular domain, an intracellular domain, and a hydrophobic transmembrane domain that spans the cell membrane seven times. Receptor activation also induces the formation of receptor clusters which are internalized and then either degraded in lysosomes or shuttled back to the cell surface.
The GnRHR differs from other G-protein coupled receptors in that it has a relatively short intracellular carboxy terminal tail that slows receptor internalization and prevents rapid desensitization. A substantial amount is known about the intracellular pathways that are downstream of GnRH receptors in the pituitary gonadotropes.
Activation of these pathways ultimately results in the stimulation of gonadotropin biosynthesis and secretion. Available data suggest that activation of the GnRHR may regulate downstream signaling systems in a cell-specific manner. In contrast to effects in the pituitary, activation of GnRH receptors in peripheral tissues has been shown to preferentially activate the G a i pathway which inhibits cAMP production. While it is possible that cell-specific post-translational splicing may occur, it has been proposed that variations in phosphorylation or glycosylation state are more likely explanations for the observed functional differences.
Multiple additional mechanisms have been proposed by which variable cell-specific GnRHR signaling may be achieved. As one possibility, intracellular signaling may also differ based on the identity of the ligand which is bound to the receptor as this will determine conformational changes which will ultimately impact signaling.
For example, although cetrorelix is widely regarded to be a competitive antagonist, it has been shown to act as an agonist on peripheral GnRH receptors. GnRH1 is more effective than GnRH2 in positively responding prostate carcinoma cell lines, while GnRH2 is more effective in negatively responding cell lines.
Signaling may also be altered by ligand affinity. Although native GnRH has the same affinity for pituitary and placental GnRH receptors, the GnRH agonist buserelin binds to pituitary receptors with over fold higher affinity.
GnRH dose and the number of cell-surface GnRH receptors may also impact signaling and, thereby, effects on cellular physiology. GnRHR expression in the gonadotrope is markedly upregulated by GnRH itself, as well as by estrogen, progesterone, and androgens.
Cell-specific differences in regulation are also very likely, although currently poorly characterized. Nevertheless, it is widely accepted that pulsatile GnRH is required for GnRHR expression on the gonadotropes with higher pulse frequencies resulting in maximal stimulation. Pituitary GnRHR expression is also increased by estradiol. Progesterone has been reported to suppress GnRHR number in the pituitary gland as observed at times of high circulating levels during the female reproductive cycle and pregnancy.
Chronic stress is known to be associated with reproductive dysfunction, attributable in part to associated increases in adrenally derived glucocorticoids such as cortisol. Cortisol has been reported to disrupt GnRH pulsatility and may also have direct action at the pituitary.
Glucocorticoids have been shown to have a direct positive effect on GnRHR transcription of the mouse promoter; however, they inhibit GnRH-induced LH secretion from bovine and porcine pituitary cells.
Inhibins and activins are closely related peptides, with inhibins consisting of heterodimers of an a-subunit and b-subunit, while activins are b-subunit homodimers.
While both may be expressed in the pituitary, the majority of data suggest that inhibins are primarily products of the ovarian granulosa and luteal cells. In contrast, activins are produced in multiple tissues including the pituitary and exert their effects locally.
PACAP is also secreted by gonadotropes and folliculostellate cells in the pituitary and may therefore act as an autocrine—paracrine factor to maintain GnRHR number.
In addition, PACAP is expressed in a wide array of reproductive and non-reproductive tissues and therefore may regulate expression of type 2 GnRH receptors. Pharmacology GnRH itself and the gonadal steroids produced in response to GnRH stimulation play a role in normal reproduction and in an array of pathophysiologic states.
In response to this observation, a substantial number of GnRH analogues have been developed for therapeutic use. Naturally occurring GnRH has a half-life of 2—4 min which can largely be accounted for by breakage of the glycine-leucine bond between amnio acids 6 and 7 Fig.
GnRH agonists have a substitution for glycine at position 6 which significantly increases the plasma half-life compared to the native hormone. Some agonists also substitute ethylamide for glycine at position 10 which increases the affinity for GnRHR. GnRH antagonists have amino acid modifications at many more positions including 1, 2, 3, 6, 10, and sometimes 8 and 5.
GnRH agonists can be used in pulsatile or continuous regimens to treat estrogen-dependent conditions including endometriosis, uterine leiomyomas, precocious puberty, and menorrhagia.
Pulsatile GnRH may be used to induce puberty in patients with hypogonadotropic hypogonadism and has been used successfully to induce follicular development or sperm production with resultant pregnancy. Unfortunately, osteoporosis will develop under the low estrogen conditions induced by prolonged GnRH agonist use. Therefore, treatment is generally limited to 6 months unless some form of estrogen add-back regimen is instituted.
As a result, GnRH agonists are generally used in preparation for surgery or in the peri-menopausal woman awaiting menopause and the natural cessation of ovarian function. With the appreciation that many tissues express GnRH and GnRH receptors, these analogues may be of use for their direct action at the target tissue rather than just indirectly through decreases in gonadal steroid production. For example, GnRH analogues are also of potential use in the treatment of a wide variety of cancers which express GnRHR, including breast, pancreatic, and ovarian cancers.
It takes approximately 1—3 weeks of GnRH agonist use to obtain a fully hypogonadotropic hypogonadal state. Side-effects of GnRH agonist therapy are related to sex hormone deficiency and are similar to menopausal symptoms, including hot flushes, vaginal dryness, and osteopenia.
The original GnRH antagonists were of limited clinical utility due to their associated histamine release; however, the newer antagonists do not have this undesirable side-effect. GnRH antagonists have mainly been used to treat infertility and advanced-stage prostate cancer. More patient-friendly, orally active formulations are under development and are being studied for the treatment of a broader array of conditions. An emerging use of GnRH analogues is for fertility preservation in patients undergoing chemotherapy for cancer or rheumatologic diseases such as lupus erythematosus.
Chemotherapy-induced early menopause has been well-established in the literature and with improved survival rates especially among premenopausal patients, fertility preservation has become increasingly important. It should be noted that the efficacy of GnRH analogue treatment for fertility preservation remains controversial. Where available, oocyte freezing or embryo freezing are preferable approaches at this time.
Abnormalities in GnRH stimulation of pituitary gonadotropin secretion may present with varying degrees of hypogonadotropic hypogonadism ranging from total absence of gonadal steroid production and lack of pubertal development to the delay of puberty to infertility due to inadequate stimulation of oocyte or sperm production. Patients with hypogonadotropic hypogonadism have classically been categorized as those without anosmia termed idiopathic hypogonadotropic hypogonadism, or IHH and those with IHH and associated anosmia.
This latter group is said to have Kallmann syndrome KS. The prevalence of IHH and KS is estimated to be , to , with a male to female ratio of The number of patients who can correctly be termed to have idiopathic disorders is decreasing as investigators identify an increasing number of associated genetic defects.
Furthermore, research in this field is demonstrating that mutations in a single gene may not be reproducibly correlated with normal or abnormal smell, blurring the line between those with IHH and Kallmann syndrome.
0コメント