Adrenomedullin, a hypotensive peptide found in human pheochromocytoma, consists of 52 amino acids, has 1 intramolecular
disulfide bond, and shows a slight homology with the calcitonin gene-related peptide (CGRP). It may function as a
hormone in circulation control because it is found in blood in a considerable concentration.
NCBI Summary:
The protein encoded by this gene is a preprohormone which is cleaved to form two biologically active peptides, adrenomedullin and proadrenomedullin N-terminal 20 peptide. Adrenomedullin is a 52 aa peptide with several functions, including vasodilation, regulation of hormone secretion, promotion of angiogenesis, and antimicrobial activity. The antimicrobial activity is antibacterial, as the peptide has been shown to kill E. coli and S. aureus at low concentration. [provided by RefSeq, Aug 2014]
General function
Ligand, Hormone
Comment
Cellular localization
Secreted
Comment
Adrenomedullin: possible predictor of insulin resistance in women with polycystic ovary syndrome. Sahin I et al. (2012) The aim of the study was to investigate adrenomedullin (ADM) levels and its relation with insulin resistance in women with polycystic ovary syndrome (PCOS). Twenty-nine women with PCOS and 29 age- and body mass index (BMI)- matched control subjects were included in the study. PCOS was defined according to criteria by the Rotterdam European Society of Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM)-sponsored PCOS consensus workshop group. A full clinical and biochemical examination including basal hormones and metabolic profile was performed. Insulin resistance was calculated by using the homeostasis model assessment of insulin resistance index (HOMA-IR). Plasma ADM levels were measured by high performance liquid chromatographic (HPLC) method. Plasma ADM, fasting insulin levels and HOMA-IR were significantly higher in patients with PCOS than the control group. ADM levels were positively correlated with insulin levels and HOMA-IR index. The best cut-off value of ADM levels to identify the presence of insulin resistance (HOMA-IR≥2.7) was 30.44 ng/ml. Calculated odds ratio of insulin resistance by using logistic regression analysis, as predicted by ADM, was 0.15 (95% confidence interval, 0.037-0.628; p=0.009). In multiple regression analysis, ADM level was an independent predictor of HOMA-IR index. Our finding indicated that ADM levels increased in women with PCOS in accordance with HOMA-IR. ADM could be a significant independent determinant of insulin resistance in women with PCOS.//////////////////
Adrenomedullin: A possible regulator of germinal vesicle breakdown. Hiradate Y et al. Adrenomedullin (ADM) is a multifunctional hormone that regulates processes as diverse as blood pressure and cell growth. Although expressed in the ovary, the role of ADM in this organ is not clear. In the present study, we found the expression of ADM receptor and receptor activity-modifying proteins in mouse cumulus cells but not in the oocytes. We report that germinal vesicle breakdown (GVBD), which is required for oocyte maturation, is not inhibited by adrenomedullin alone. However, adrenomedullin in the presence of the nitric oxide donor sodium nitroprusside (SNP) significantly inhibited GVBD. Furthermore, the adrenomedullin- and SNP-dependent inhibition of GVBD was abrogated by Akt blockade. Additionally, Akt expression and phosphorylation was exhibited by ADM, suggesting that Akt signaling upstream in cumulus cells is responsible. Additionally, immunohistochemical analysis revealed that ADM was localized in the granulosa cells of developed follicles, implying the possibility that ADM physiologically affects oocyte maturation in vivo. Our results provide the evidence that adrenomedullin can act as a GVBD regulator.
Abe et al 2000 reported the expression and effect of adrenomedullin (AM) on rat granulosa cell.
The effect of
gonadotropin on the production of AM was studied in the cultured rat granulosa cells. A Northern blot
analysis of the LH receptor and adrenomedullin yielded a major hybridizing band at 5.4 kb and 1.6 kb,
respectively. In cultured rat granulosa cells, FSH significantly
induced LH receptor mRNA and suppressed AM mRNA for 4 days of culture and with the addition of
hCG after 2 days of pretreatment with FSH, AM mRNA levels were markedly suppressed. FSH and
8-Br-cAMP significantly increase LH receptor mRNA and suppress AM mRNA in a dose-dependent
manner. On the
other hand, AM stimulated a rapid rise in intracellular cAMP levels, which peaked within 15 min of
addition, in a dose-dependent manner with a maximal response seen at 100 nM. Additionally, AM
enhanced the effects of FSH, acting additionally to produce cAMP in the cells. AM may play a role in
the process of granulosa cell differentiation as a local regulator through an autocrine/paracrine
mechanism.
Moriyama T, et al 2000 reported the expression of adrenomedullin (AM) by human granulosa lutein cells and its effect on
progesterone production. Concentrations of
AM in follicular fluid collected just before ovulation were significantly higher than those in the
plasma (P<0.01). AM mRNA was expressed in granulosa cells at the preovulatory stage. Cultured
granulosa lutein cells secreted immunoreactive AM. With immunohistochemical staining, it was
revealed that AM was most abundantly expressed in granulosa lutein cells at the midluteal phase. No
appreciable staining for AM was observed in granulosa cells in primordial and preantral follicles,
whereas immunolocalization of AM was noted in granulosa cells of dominant follicles although it was
not as prominent as in granulosa lutein cells at the midluteal phase. Furthermore, addition of AM to
cultured granulosa lutein cells augmented progesterone secretion in a dose-dependent manner.
These results suggest that AM is transcribed and secreted in human granulosa lutein
cells as a local factor to enhance progesterone production by those cells.
Coexpression of Adrenomedullin and Its Receptors in the Reproductive System of the Rat: Effects on Steroid Secretion in Rat Ovary. Li YY et al. The present study demonstrates the expression of adrenomedullin (ADM) in the reproductive system of the female rat and its effect on the secretion of estradiol and progesterone. Ovarian ADM and Adm mRNA levels were decreased at estrus while oviductal Adm mRNA levels were low at proestrus. Both tissues were shown to co-express mRNAs encoding the calcitonin receptor-like receptor and receptor activity modifying protein 1 (Ramp1), Ramp2 and Ramp3. Gel filtration chromatography of ovarian extracts showed two peaks, with the predominant one eluting at the position of authentic rat ADM (1-50) at estrus and at the position of ADM precursor at diestrus. Positive ADM immunostaining was localized in the granulosa and theca cells of the follicle and corpora lutea of the ovary. ADM inhibited FSH-induced estradiol secretion in 2-day old follicles and also suppressed eCG-stimulated progesterone release in corpora lutea. The inhibitory effect of ADM on the follicles and the corpora lutea was abolished by CALCA (8-37) and ADM (22-52) respectively. The presence of ADM and the gene expression of ADM and its receptor components in female reproductive system suggest a paracrine effect of ADM on ovarian steroidogenesis.
Expression regulated by
FSH
Comment
Marinoni E, et al 2000 reported changes in plasma adrenomedullin levels during the menstrual cycle.
The adrenomedullin profile during ovarian cycle
was similar to that of LH; plasma adrenomedullin increased from 10.9 pg/ml at the 7th day to 15.1
pg/ml at the 14th, and decreased to 8.5 pg/ml in the subsequent menses. Since it has
been demonstrated that adrenomedullin is involved in the regulation of hypothalamus-pituitary-adrenal
gland and its secretion is regulated by sex hormones we speculate that adrenomedullin could also play
a role in regulating the hypothalamus-pituitary-ovary feedback. Alternatively it may be involved in the
regulation of fluid and electrolyte homeostasis during the menstrual cycle.
Adrenomedullin in rat follicles and corpora lutea: expression, functions and interaction with endothelin-1. Li L et al. ABSTRACT: BACKGROUND: Adrenomedullin (ADM), a novel vasorelaxant peptide, was found in human/rat ovaries. The present study investigated the interaction of ADM and endothelin 1 (ET-1) in follicles and newly formed corpora lutea (CL) and the actions of ADM on progesterone production in CL during pregnancy. METHODS: The peptide and gene expression level of adrenomedullin in small antral follicles, large antral follicles and CL was studied by real-time RT-PCR and EIA. The effect of ADM treatment on oestradiol production in 5-day follicular culture and on progesterone production from CL of different pregnant stages was measured by EIA. The interaction of ADM and ET-1 in follicles and CL at their gene expression level was studied by real-time RT-PCR. RESULTS: In the rat ovary, the gene expression of Adm increased during development from small antral follicles to large antral follicles and CL. In vitro treatment of preantral follicular culture for 5 days with ADM increased oestradiol production but did not affect follicular growth or ovulation rate. The regulation of progesterone production by ADM in CL in culture was pregnancy-stage dependent, inhibitory at early and late pregnancy but stimulatory at mid-pregnancy, which might contribute to the high progesterone production rate of the CL at mid-pregnancy. Moreover, the interaction between ADM and ET-1 at both the production and functional levels indicates that these two vasoactive peptides may form an important local, fine-tuning regulatory system together with LH and prolactin for progesterone production in rat CL. CONCLUSIONS: As the CL is the major source of progesterone production even after the formation of placenta in rats, ADM may be an important regulator in progesterone production to meet the requirement of pregnancy.
Intrafollicular concentration of adrenomedullin is associated with IVF outcome. Marinoni E et al. Objective. To test the hypothesis that serum or intrafollicular concentrations of adrenomedullin (AM) would correlate with reproductive outcomes in in vitro fertilisation (IVF) cycles. Design. Serum and follicular fluid samples were collected during transvaginal oocyte retrieval. The follicular fluid was individually aspirated, and the presence of oocyte was recorded. AM concentrations were measured using an enzyme-linked immunosorbent assay. Setting. Department of Gynaecology, Perinatology and Child Health, 'Sapienza' University of Rome, Italy. Patients. Eighty women undergoing IVF for primary infertility aged 18-45 years. Main Outcome Measures. AM concentrations in plasma and follicular fluid were correlated to follicular fluid volume, presence of oocyte, oocyte maturation, embryo grading, fertilisation and pregnancy rates, live-birth rate and plasma estrogen concentration. Results. Monofollicular fluid AM concentrations did not differ between follicles containing oocyte and those without oocyte; however, AM concentrations were lower in follicles that resulted in pregnancy than in those that failed. Serum but not follicular fluid AM concentrations correlated with serum estrogen levels. Follicular fluid AM correlated with plasma AM levels. Conclusion. We conclude that higher level of AM in the follicular fluid appears to be associated with a negative outcome in IVF treatment.
Abe K, et al 2000 reported the expression of adrenomedullin (AM) in the human corpus luteum.
Northern blot analysis of AM, receptor
activity-modifying protein 2 (RAMP2), and LH/hCG receptor mRNA in human
samples.
The AM and LH/hCG receptor mRNA levels were
low in the mature follicle but increased in the corpus luteum of the
mid-luteal phase and were maintained during early pregnancy. A single
transcript of 0.8 kb for RAMP2 was also seen in the follicle and corpus
luteum, the level of RAMP2 mRNA was relatively high in the preovulatory
follicle and RAMP2 was present in the corpus luteum.
In conclusion, the expression of AM, its receptor, and LH/hCG receptor may be
an important component in the process of development and differentiation of
the corpus luteum.
Expression of adrenomedullin in human ovaries, ovarian sex cord-stromal tumors and cultured granulosa-luteal cells. Liu J et al. The aim of the present study was to characterise the expression pattern of the multifunctional vasoactive peptide adrenomedullin (ADM) in human ovarian tumors, and to find hormonal regulators of ADM expression in human ovaries. The expression of ADM messenger RNA (mRNA) was higher in granulosa cell tumors than in fibrothecomas and normal ovaries, as analysed by Northern blots. In normal ovaries, ADM immunoreactivity was localised in both granulosa and thecal cells. Eight of the 90 granulosa cell tumors (9%) showed moderate and 53 (59%) weak ADM immunoreactivity, whereas 27% (11/41) of the fibrothecomas displayed weak ADM staining. FSH, protein kinase A activator (Bu)(2)cAMP, prostaglandin E(2) (PGE(2)), activin A and the broad protein kinase regulator staurosporine decreased ADM mRNA accumulation in cultured granulosa-luteal cells time- and dose-dependently. FSH, (Bu)(2)cAMP and PGE(2) increased progesterone secretion and the accumulation of the steroidogenic acute regulatory protein mRNA in these cells. In conclusion, ADM is expressed in normal human ovaries and sex cord-stromal tumors, particularly in those of granulosa cell origin. FSH, PGE(2,) (Bu)(2)cAMP and activin A suppress ADM gene expression in granulosa-luteal cells. Expression of ADM in human ovaries and its hormonal regulation in granulosa cells suggests a paracrine role for ADM in ovarian function.
Follicle stages
Antral, Preovulatory, Corpus luteum
Comment
Adrenomedullin and vascular endothelial growth factor production by follicular fluid macrophages and granulosa cells.
Balasch J,et al 2004 . Human follicular fluid contains several substances, such as cytokines and growth factors, which may affect follicular growth and maturation. The present study examines the relative contribution of macrophages and granulosa cells in the production of vascular endothelial growth factor (VEGF) and adrenomedullin in the human ovulatory follicle. METHODS: Both follicular fluid samples and blood samples were obtained at the time of oocyte retrieval following ovarian stimulation from 20 women undergoing IVF treatment because of male infertility. Human follicular fluid macrophages and luteinized granulosa cells were obtained from pooled follicular fluid of individual patients. Accumulation of VEGF and adrenomedullin in the culture medium of the isolated macrophages and human granulosa cells was determined at variable time intervals ranging from 0 to 48 h. Plasma and follicular fluid concentrations of VEGF and adrenomedullin were also measured. RESULTS: The follicular fluid concentrations of VEGF and adrenomedullin were significantly higher than those found in plasma. After 48 h, accumulation of VEGF in the culture medium of follicular fluid macrophages was significantly higher than that released in the culture medium of luteinized granulosa cells. In contrast, the production rate of adrenomedullin by follicular fluid macrophages was similar to that found in granulosa cells. VEGF secreted by follicular fluid macrophages increased progressively within 48 h of cell culture. A similar response pattern was observed with the culture medium of luteinized granulosa cells, but with lower production rates. CONCLUSIONS: This study suggests for the first time that both luteinized granulosa cells and macrophages actively secrete VEGF and adrenomedullin into follicular fluid in the human ovary.