Hormones, Cytokines And Prostaglandins Which Increase hCG Synthesis Or Release From Syncytiotrophoblast Cells

Hormones, Cytokines And Prostaglandins Which Increase hCG Synthesis Or Release  From Syncytiotrophoblast Cells

 

Many substances, hormones, cytokines and prostaglandins are known to stimulate the production or release of hCG from maternal syncytiotrophoblast cells in the first trimester of pregnancy.

1. Gonadotrophin Releasing Hormone (GNRH)

1a. Pulsatile release of hCG into the medium. Pulse amplitude and frequency were increased in response to GNRH in higher dosage (1).

1b. GNRH stimulated hCG secretory response by 80%. IL1 beta stimulated a rapid and transient hCG stimulatory response increase approximately 150%, but lower concentrations were ineffective. Combined treatment stimulated response by 150%. GNRH and IL-1 beta produce an increased stimulation but by different pathways. 8-12 weeks placental trophoblast used (2).

2. Epidermal Growth Factor (EGF)

2a. EGF 7-10 week (gestational weeks placentae).  In superficial explants, short (1-4 minutes)
pulses of EGF increased both rate and amplitude of spontaneous pulsatility of hCG.   
The frequency increased from 3 to 5 hours.  This effect was dose-dependent and the
concentration of 50ng/ml was the lowest tested and the most effective.  In explants cultured
for 24 hours EGF caused a two-fold increase in hCG secretion compared to controls. EGF
added daily for the first week  caused 180% increase in hCG secretion.

2b. EGF stimulated proliferate potential of cytotrophoblast in early (4-5 week)  placental
explants.  The EGF stimulation of trophoblast proliferation was apparent at a 12 hour EGF
treated period.  By contrast, 6-12 week placental explants did not respond to EGF increase
in trophoblast proliferation.  Instead, in early placental explant culture, EGF stimulated
hCG and Human Placental Lactogen (HPL) secretion with a lag period of 72 hours,
whereas, very early placental explants did not respond to EGF with increase in hCG and
HPL secretion. Therefore, EGF stimulated trophoblast proliferation in 4-5 week placenta
and stimulates differentiated trophoblast function in 6-12 week placentae (4).

2c. EGF binding sites and EGFR production increase in human placentae throughout the gestation period (5).

3. Parathyroid Hormone (1-34PTH)

Gestational age-dependent effects of parathyroid hormone (1-34 PTH) were noted.  
 In static cultures 1-34 PTH stimulated hCG secretion in 7-9 week placentae in a  biphasic
fashion, the maximal effect being noted at 10-25ng/ml concentration (250-270%) while at 1
and 100ng/ml the effect was mild.  Effects of 1-34 PTH at 11-14 weeks were inhibitory.  In
static cultures at 7-9 weeks the stimulatory effects of 25ng 1-34 PTH was increased by 70%
when EGF 100 ng/ml was added (6).

4. Oxytocin (OT) Arginine-Vasopressin (AVP) and Prolactin (PRL) Effects on hCG

In static cultures OT and AVP significantly increase hCG secretion, whereas PRL had no
effect.  In superperfusion, one minute pulses of OT induce a significant 2 to 10 fold rise in
hCG pulse amplitude.  PRL pulses caused a progressive inhibition of spontaneous hCG
pusatility (7).

5. Calcium

Secretion of hCG by first trimester human placental minces.  Depletion of calcium (Ca) in
the medium by addition of EGTA resulted in a dramatic decrease in the levels of
immunoreactive hCG in the medium with consequent accumulation of hCG in the tissue.  
Calcium is essential for normal secretion of hCG by human placentae (8).

6. c’AMP

Any factor which increases c’AMP in trophoblast tissue will increase maternal hCG secretion (9, 10) .
Factors known to increase c’AMP in trophoblast cells:
(i) Catecholamines
(ii) GNRH
(iii) hCG itself, hCG variants,
(iv) Prostaglandin E2

7. Catecholamines stimulate c’AMP in early Trophoblast Cells

7a. The catecholamine Epinephrine stimulated adenylate cyclase activity from 10 weeks of gestation to term (11).

7b. High density of B adrenergic receptors in human placentae composed of B1 and B2 receptors. It is likely that cell size or membrane surface area changes contribute greatly to the decrease in beta adrenergic receptor densities observed with increasing gestational age (12). 3H-DNA binding to early human placentae, the binding capacity of early crude placental membrane is about three times higher than described in term placentae (13).

8. hCG and its Variants Stimulate c’AMP in early Trophoblast Cells

The acute in vitro effects of human chorionic gonadotrophin (hCG) on human placental
gylcogen metabolism have been studied in immature placental villi (8-20 weeks) in short
term culture.  hCG elicited within 15 minutes of culture an acute glycogenolytic response in
placental tissue which included a decrease in placental glycogen, an activation of the
glycogen phosphorylase enzyme system and a pronounced elevation in the cyclic AMP concentration of the placenta.  (14)

9. hCG Variants

The principal difference between hCG and other glycoprotein hormones (leuteinizing hormone LH), follicule stimulating hormone (FSH), thyroid stimulating hormone (TSH) is the large 31 amino acid tail, the -carboxyterminal portion (-CTP). LH is ten times more potent than intact hCG at stimulating the TSH receptor; mutant hCG’s lacking the -CTP were much more potent than intact hCG in stimulating the release of c’AMP when they combined with human TSH and LH receptors (15).
Normal human placenta express hCG/LH receptor gene (16).

10a. Prostaglandin E2 Stimulates c’AMP in early Trophoblast Cells

The acute in vitro effects of Prostaglandin E2 on human placental glycogen metabolism have been studied in immature placental villi in short term culture. 10 ng/ml Prostaglandin E2 induced a similar glycogenolytic effect including a larger decrease in placental glycogen than 50 iu/ml of hCG and an increase in tissue cyclic AMP concentration (14).

10b. hCG itself has also been shown to stimulate PGE2 synthesis in 9-12 week placentas at physiological conditions. The rate of PGE2 synthesis increased with a longer incubation period, particularly in placentas of younger gestation. Significant stimulation of PGE2 synthesis occurred at 104 iu/1 hCG and continued to increase in a dose-dependent manner up to 5 x 106 iu/1 as seen in 9-10 week placental organ cultures. There was considerable variation of PG production between placentas of the same gestation (17).

11. Interleukin-1 Stimulates hCG Secretion

IL1 (10-9m) increased basal hCG secretion in placental trophoblast. The response peaked within 25 minutes after IL1 perfusion was initiated, and hCG secretion returned to basal concentration 10 minutes later. IL1 (10-9m) stimulated a rapid and transient hCG secretory response. hCG release increased by approximately 150% in response to the cytokine, but lower concentrations were ineffective. IL1 (10-9m) is within the physiological range. 8-12 week placental trophoblast (18).

12. Tumour Necrosis Factor Alpha (TNF ALPHA) Stimulates hCG Secretion

Trophoblast stimulated with rTNF alpha released hCG in a dose-dependent fashion. Simultaneous stimulation of trophoblasts (placentas at 7-9 weeks gestation) with rTNF alpha and IL-1 alpha resulted in synergistic enhancement of IL-6 release, subsequently leading to enhanced hCG release. Although TNF alpha and IL-1 share the intracellular signalling pathway, a comparative study of their potency to stimulate IL-6 production demonstrated that the level induced by rTNF alpha is much lower than the level induced by rIL-1. Similar results were obtained with regard to the capacity of these cytokines to induce hCG release. rTNF alpha induced IL-6 release at doses greater than 200 ng/ml while IL-1 alpha induced IL-6 releases at doses 2.0 ng/ml (19).

13. Human Macrophage Colony-Stimulating Factor (M-CSF)

When human cytotrophoblast cells in the early stage of pregnancy (6-11 week human
villous tissue used) were cultured in a serum-free medium in the presence of M-CSF, the
cytotrophoblast cells fused and formed a typical syncytiotrophoblast. On the other hand,
cytotrophoblasts incubated with anti-M-CSF antibody showed hardly any
syncytiotrophoblast formation.
 
 When cytotrophoblasts were incubated in the presence of M-CSF  the supernatant of the
culture showed an increase in human chorionic gonadotrophin and human placental
lactogen (HPL) levels in proportion to the concentration of M-CSF  added.  When
cytotrophoblasts were incubated in the presence of anti-M-CSF antibody or anti-FMS
antibody, hCG and HPL secretion were suppressed. Thus, M-CSF was morphologically and
endocrinologically found to induce the differentiation of chorionic cells and hCG synthesis
(20).

14. Transforming Growth Factor B1 (TGFB-1) Suppresses hCG Release

Trophoblast-derived TGFB-1 suppresses cytokine but not GNRH induced release of hCG
by normal human 7-9 week trophoblasts.  Trophoblast produced predominantly a latent
rather than an active form of TGFB-1 (21).
 rTGFB-1 markedly suppressed rIL-1 alpha and rTNF alpha and IL-6 induced hCG release.  
In contrast to the TGFB-1 mediated regulatory activity on IL-6 and hCG release, TGFB-1
exerted no inhibitory or augmenting effect on IL-6 or hCG production.  These findings,
together with TGFB-1’s effect on GNRH-induced hCG release exclude the possibility that
rTGFB-1 is toxic to trophoblasts and thereby reduces IL-6 and hCG release.  This indicates
that TGFB-1, produced by trophoblasts, platelets and monocytes in the placenta might act
as a physiological regulator of cytokine-dependent hCG release mechanism in an autocrine
or paracrine fashion (21).

These are some of the organic substances which increase hCG synthesis from
syncytiotrophoblast cells in early pregnancy: gonadotrophin releasing hormone, epidermal
growth factor, parathyroid hormone, oxytocin arginine-vasopressin hormones, cyclic AMP,
catecholamines, hCG itself and variants of hCG, Prostaglandin E2, Interleukin-1", tumour
necrosis factor alpha and macrophage colony-stimulating factor.  Prostaglandin E2 is the
only substance in this group that is known to cause nausea and vomiting. For further
information please see appendix B.

REFERENCES

1. SZILAGYI A, BENZ R, ROSSMANITH W G.
The human first term placenta in vitro: regulation of hCG secretion by GNRH and its antagonist.
Gynaecol Endocrinol. 1992;6 (4):293-300.

2. STEELE G L, CURRIE W D, LEUNG E H, YUEN B H, LEUNG P C.
Rapid stimulation of hCG secretion by Interleukin I beta from perfused first trimester trophoblast.
J. Clin Endocrinol and Metab. 1992;75:783-788.

3. BARNEA E R, FELDMAN D, KAPLAN M, MORRISH D W.
The dual effect of epidermal growth factor upon hCG secretion by the first trimester placenta in vitro.
J. Clin Endocrinol Metab. 1990;71 (4):923-8.

4. MARUO T, MATSUO H, MURATA K, MOCHIZUKI M.
Gestational age-dependent dual action of epidermal growth factor on human placenta early in gestation.
J. Clin Endocrinol Metab. 1992;75 (5):136-7.

5. CHEN CHU FUNG, KURACHI H, FUJITA Y, TERAKANA N, MIYAKE A, TANIZAWA O.
Changes in epidermal growth factor receptor and its messenger ribonucleic acid levels in human placenta and isolated trophoblast cells during pregnancy.
J. Clin Endocrinol Metab. 1988;67:1171-117.

6. SHURTZ-SWIRSKI R, CHECK J H, BARNEA E R.
Effect of 1-34 human parathyroid hormone upon first trimester placental hCG secretion in vitro: potentiation by human growth factor.
Human Reproduct. 1993;8 (1):107-11.

7. TAL J, KAPLAN M, SHARF M, BARNEA E R.
Stress-related hormones (OT, AVP, HPL) affect hCG from the early
human placenta in vitro.
Human Reproduct. 1991;6 (6):766-9.

8. SHARMA S C, RAO A J.
Role of calcium in secretion of chorionic gonadotrophin by first trimester human placenta.
Indian Journal of Experimental Biology. 1992;30(11):1105-1110.

9. HUSSA R O M, STOREY T, PATTILLO R A.
Cyclic Adenosine Monophosphate stimulated secretion of human chorionic gonadotrophin and oestrogens by human trophoblast in vitro.
J. Clin Endocrinol Metab. 1974;38:338-340.

10. HANDWERGER S, BARRETT J, TYNEY L, SCHOMBERG D.
Differential effect of cyclic adenosine Monophosphate on the secretion of human placental lactogen and human chorionic gonadotrophin.
J. Clin Endocrinol Metab. 1973;36:1268-1270.

11. WHITSETT J A, JOHNSON C L, NOGUCHI A, DAVOREC-BECKERMAN C, COSTELLO M.
Beta adrenergic receptors and catecholamine sensitive adenylate cyclase of the human placenta.
J. Clin Endocrinol Metab. 1980;50:27-32.

12. MOORE J J, WHITSETT J A.
The -adrenergic receptor in mammalian placenta: species differences and ontogency.
Placenta. 1982;3:257-268.

13. FALKAY G, KOVACS L.
Beta-adrenergic receptors in early human placenta. Characterisation of 3H- Dihydroalprenolol binding.
Life Sciences. 1983;32:1583-1590.

14. DEMERS L M, GABBE S G, VILLEE C A, GREEP R O.
Human chorionic gonadotrophin-mediated glycogenolysis in human placental villi:
a role of prostaglandins.
Biochem Biophys Acta. 1973;313:202-210.

15. YOSHIMURA M, PEKARY A E, PANG X P, BERG L, GOODWIN T M, HERSHMAN J M.
Thyrotrophic activity of basic isoelectric forms of human chorionic gonadotrophin extracted from hydatidiform mole tissues.
J. Clin Endocrinol Metab. 1994;78:862-866.

16. SHI Q J, LEI Z M, RAO CH V, LIN J.
Novel role of human chorionic gonadotrophin in differentiation of human cytotrophoblasts.
Endocrinol. 1993;132:1387-1395.

17. NORTH R A, WHITEHEAD R, LARKINS R G.
Stimulation by human chorionic gonadotrophin of prostaglandin synthesis by early human placental tissue.
J. Clin Endocrinol Metab. 1991;73:60-70.

18. STEELE G L, CURRIE W D, LEUNG E H, YUEN B H, LEUNG P C K.
Rapid stimulation of human chorionic gonadotrophin secretion by Interleukin-1 from perifused first trimester trophoblast.
J. Clin Endocrinol Metab. 1992;75:783-788.

19. LI Y, MATSUZAKI N, MASUHIRO K, KEMEDA T, TAWIGUCHI T, SAJI F,
YONE K, TANIZAWA O.
Trophoblast-derived tumour necrosis factor-α induces release of Human Chorionic Gonadotrophin using Interleukin-6 (IL-6) and IL-6 receptor-dependent system in the normal human trophoblast.
J. Clin Endocrinol Metab. 1992;74:184-191.

20. SAITO S, SAITO M, ENOMOTO M, ITO A, MOTOYOSHI K, NAKAGANA T, KHIJO M.
Human macrophage colony-stimulating factor induces the differentiation of trophoblast.
Growth Factors. 1993;9:11-19.

21. MATSUZAKI N, LI Y, MASUHIRO K, TOUSHUN J O, SHIMOYA K,
TANIGUCHI T, SAJI F, TANIZAWA O.
Trophoblast-derived transforming growth factor B suppresses cytokine-induced but not gonadotrophin-releasing hormone induced release of Human Chorionic Gonadotrophin by normal human trophoblasts.
J. Clin Endocrinol Metab. 1992;74:211-216.

 

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