Corticotropin (ACTH), synthesized by the anterior pituitary gland, stimulates the adrenal cortex. Human ACTH has a
molecular weight of 4,541 and contains 39 amino acids. It has structural similarities to melanotropin
(melanocyte stimulating hormone; MSH). Work on the structure of the ACTH gene by restriction enzyme techniques showed that 6
hormones are derived from one gene: ACTH, lipotropin, alpha-MSH, beta-MSH, endorphin, and one other. Thus,
extensive amino acid differences between these hormones were not adequate evidence for their being distinct. ACTH
and beta-lipotropin (beta-LPH) are derived from a large precursor peptide. Each of these hormones is known to include
smaller peptides having distinct biological activities: alpha-melanotropin (alpha-MSH) and corticotropin-like
intermediate lobe peptide (CLIP) are formed from ACTH; gamma-LPH and beta-endorphin are peptide components of
beta-LPH. Beta-MSH is contained within gamma-LPH. The precursor peptide was called proopiomelanocortin
(POMC).
NCBI Summary:
This gene encodes a preproprotein that undergoes extensive, tissue-specific, post-translational processing via cleavage by subtilisin-like enzymes known as prohormone convertases. There are eight potential cleavage sites within the preproprotein and, depending on tissue type and the available convertases, processing may yield as many as ten biologically active peptides involved in diverse cellular functions. The encoded protein is synthesized mainly in corticotroph cells of the anterior pituitary where four cleavage sites are used; adrenocorticotrophin, essential for normal steroidogenesis and the maintenance of normal adrenal weight, and lipotropin beta are the major end products. In other tissues, including the hypothalamus, placenta, and epithelium, all cleavage sites may be used, giving rise to peptides with roles in pain and energy homeostasis, melanocyte stimulation, and immune modulation. These include several distinct melanotropins, lipotropins, and endorphins that are contained within the adrenocorticotrophin and beta-lipotropin peptides. The antimicrobial melanotropin alpha peptide exhibits antibacterial and antifungal activity. Mutations in this gene have been associated with early onset obesity, adrenal insufficiency, and red hair pigmentation. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jan 2016]
General function
Ligand, Hormone
Comment
Cellular localization
Secreted
Comment
family123
Ovarian function
Ovulation, Steroid metabolism, Luteinization
Comment
Gregoraszczuk EL et al reported beta-endorphin inhibits progesterone secretion by porcine granulosa cells during follicle development.Faletti A, et al reported that beta-endorphin inhibits prostaglandin synthesis in rat ovaries
and blocks induced ovulation
in ovaries isolated from pregnant mare's serum gonadotropin/human
chorionic gonadotropin(PMSG/hCG)-primed immature rats. An intrabursal
injection of the opioid (0.084 microgram) was given 4 hours after hCG and the
number of oocytes within the oviducts on the following morning was reduced (P <
0.05). The same effect was also attained with an intraperitoneal (IP) injection (0.5
microgram).
Kato T et al reported the effect of beta-endorphin on cAMP and progesterone
accumulation in rat luteal cells.
Facchinetti F, et al 1986 reported that enkephalin enhances follicle-stimulating hormone-dependent progesterone production from cultured granulosa cells.
Expression regulated by
FSH, LH, Growth Factors/ cytokines
Comment
Przala J, K et al 1999 reported that large luteal cells are a major source of beta-endorphin in the porcine
corpus luteum, where its release may be affected by gonadotropins (possibly LH) and TNFalpha.
Kaminski T et al 2000 reported that FSH drastically increased beta-END-LI release by granulosa cells (GCs) from large follicles in a dose-dependent
fashion. This stimulatory effect of the gonadotrophin was inhibited by the
highest dose of P-4 (10(-5) M). The effect of PRL and the steroids added to
the cultures on beta-END-LI release was negligible. FSH- or PRL-induced P-4
Secretion by GCs was essentially abolished by both opoid agonist FK 33-824 and naloxone (NAL). However,
androstenedione (A(4)) and testosterone output by the cells was greatly
potentiated by FK 33-824. In the presence of NAL, FSH or PRL, A(4) release
stimulated by FK 33-824 was suppressed to the basal level.
Lovegren ES et al 1991 studied ovarian contents of immunoreactive beta-endorphin and
alpha-N-acetylated opioid peptides in rats.
Beta-Endorphin was measured by radioimmunoassay in homogenates of ovaries from immature Sprague-Dawley rats (21-29 days of age) and found to be present
at levels of about 0.6-0.7 ng/ovary. After administration of PMSG there was
approximately a 4-fold increase (2-3 ng/ovary) in total ovarian immunoreactive
(ir) beta-endorphin 48 h after injection. Analysis of follicular fluid from similarly
treated rats indicated about the same amount of ovarian ir-beta-endorphin (2-3
ng/ovary) as in ovarian homogenates, suggesting that most of the ir-beta-endorphin
is localized in follicular fluid of PMSG-primed immature rats. Immature rats were
made pseudopregnant by administration of hCG 48 h after PMSG, and at 24 h after
injection of hCG there was a slight, but significant and reproducible, increase in
the ovarian content of ir-beta-endorphin.
Ovarian localization
Oocyte, Granulosa, Follicular Fluid
Comment
Tepper R, et al 1990 reported
the finding of beta-endorphin levels in the follicular fluid of human oocytes fertilized in vitro.
Jacobs RA, et al. (1991) reported that immunoreactive adrenocorticotrophin is present in the ovary and in particular the oocyte of several mammalian species, including humans, cows, pigs, pregnant and non-pregnant sheep.
Follicle stages
Secondary, Antral, Preovulatory, Corpus luteum
Comment
Adams ML et al 1989 reported the ontogeny of immunoreactive beta-endorphin and
beta-lipotropin in the rat ovary.
Aleem et al reported the presence of immunoreactive beta-endorphin in human ovaries.
Beta-endorphin (beta-EP) immunostainable cells were demonstrated in human
ovarian tissue using a non-cross-reacting anti-beta-EP serum and the
avidin-biotin-peroxidase detection technique. In ovaries from ovulating and
premenopausal women, beta-EP immunoreactivity was localized in the luteinized
cells of theca interna of maturing follicles with almost negligible staining in
granulosa cells; cells of primary follicles did not stain. In corpora lutea, luteinized
cells in both theca interna and granulosa, layers were equally positive. In
postmenopausal ovaries, staining was detectable only in scattered luteinized
stromal cells.
Lolait SJ, et al 1985 reported ovarian immunoreactive beta-endorphin and estrous cycle in the
rat.
Two anti-beta-endorphin antisera, both recognizing different
antigenic determinants of human-beta-endorphin, showed intense
immunofluorescence staining of cells localized predominantly in ovarian corpora
lutea. At proestrus, both large and small luteal cells stained positively but only the
large luteal cells were immunofluorescence positive at other stages of the estrous
cycle. In addition, less intense staining of granulosa cells was occasionally
observed in secondary and antral follicles; scattered cells in the interstitium were
also weakly positive. In contrast, cells of primordial and primary follicles, and
those of theca tissue were consistently negative.
Shaha C et al 1984 reported the demonstration of immunoreactive beta- endorphin in the
ovaries of neonatal, cyclic, and pregnant mice.
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: human
Mutation name: None
type: naturally occurring fertility: subfertile Comment: Family-Based Analysis of Candidate Genes for Polycystic Ovary Syndrome. Ewens KG et al. Context: Polycystic ovary syndrome (PCOS) is a complex disorder having both genetic and environmental components. A number of association studies based on candidate genes have reported significant association, but few have been replicated. D19S884, a polymorphic marker in fibrillin 3 (FBN3), is one of the few association findings that has been replicated in independent sets of families. Objective: The aims of the study are: 1) to genotype single nucleotide polymorphisms (SNPs) in the region of D19S884; and 2) to follow up with an independent data set, published results reporting evidence for PCOS candidate gene associations. Design: The transmission disequilibrium test (TDT) was used to analyze linkage and association between PCOS and SNPs in candidate genes previously reported by us and by others as significantly associated with PCOS. Setting: The study was conducted at academic medical centers. Patients or Other Participants: A total of 453 families having a proband with PCOS participated in the study. Sisters with PCOS were also included. There was a total of 502 probands and sisters with PCOS. Intervention(s): There were no interventions. Main Outcome Measure(s): The outcome measure was transmission frequency of SNP alleles. Results: We identified a six-SNP haplotype block spanning a 6.7-kb region on chromosome 19p13.2 that includes D19S884. SNP haplotype allele-C alone and in combination with D19S884-allele 8 is significantly associated with PCOS: haplotype-C TDT chi(2) = 10.0 (P = 0.0016) and haplotype-C/A8 TDT chi(2) = 7.6 (P = 0.006). SNPs in four of the other 26 putative candidate genes that were tested using the TDT were nominally significant (ACVR2A, POMC, FEM1B, and SGTA). One SNP in POMC (rs12473543, chi(2) = 9.1; Pcorrected = 0.042) is significant after correction for multiple testing. Conclusions: A polymorphic variant, D19S884, in FBN3 is associated with risk of PCOS. POMC is also a candidate gene of interest.