USA HCG
REFERENCE SERVICE
PITUITARY hCG
Click on link below to show the most
recent publications (requires Adode Acrobat) -
Snyder JA, Haymond
S, Parvin CA, Gronowski AM, Grenache DG. Diagnostic considerations in
the measurement of human chorionic gonadotropin in aging women. Clin
Chem 2005, 51:1830-35
Cole LA. Background hCG, Clin Chem
51: 1765-66, 2005.
Cole LA, Khanlian SA,
Giddings A, Butler SA, Muller CY, Hammond C, Kohorn E.
Gestational trophoblastic diseases: 4. Presentation with Persistent Low
Positive Human Chorionic Gonadotropin Gynecologic Oncology, in press
2006
Pituitary hCG
It has long been
known that the gonadotrope cells of the pituitary produce LH and FSH
under the control of hypothalamic GnRH. GnRH is regulated by ovarian
steroids. With age the ovary starts to fail, limiting progestagen and
estrogen feedback to control GnRH. Starting in peri-menopause and then
intensifying in menopause, GnRH production looses steroidal control. As
a result, continuous GnRH stimulation of gonadotrope cells then occurs,
leading to elevate LH and FSH production. Under these hyper-stimulation
conditions, the pituitary may secrete an hCG-like molecule (7-9).
Pituitary hCG is the cause of hCG production in non-pregnant women, most
notably in those peri-menopause and post-menopause (4-9). Not
surprisingly, pituitary hCG is suppressed by estrogen/progestagen
contraceptive pills (4,6,7,9).
Pituitary hCG production can also be demonstrated in normal menstruating
women at the time of the hCG peak. We recently examined urine from 40
women. LH was measured during the course of 1 - 5 menstrual cycles
monitored. As found, in 1 of 3 menstrual cycles, hCG was detectable in
urine (>1 mIU/ml). At no time was hCG exceeding 3 mIU/ml detected.
Pituitary hCG was discovered almost 30
years ago. The first report was in 1976 by Chen et al. (10).
These findings were confirmed in 1983 by Hartree et al (11). In
1987 Odel et al. (3) found that pituitary hCG production was
pulsatile like that of LH and FSH. In that same year Stenman et al. (4)
showed that pituitary hCG production, like LH and FSH was modulated by
GnRH and sex steroids. It was not until 1996 that Birken et al.
(8) showed that pituitary hCG had N-linked sugar side chains resembling
those of LH rather than those of pregnancy hCG; thus the wording
hCG-like molecule. It has taken almost 30 years to elaborate on the
clinical significance of basic science discoveries.
The use of a 5 mIU/ml serum hCG cut-off for demonstrating pregnancy is a
standard. While this cut off value has been widely used for many years
there have only been limited studies, in terms of numbers of
non-pregnant women, to support it (2-5). A recent study examines 240
non-pregnant women of optimal viable age for testing, 18-40 years, have
been evaluated (1). One case had an hCG of 4.6 mIU/ml. While the 97.5th
percentile for this group was 2.5 mIU/ml, the bulk of cases had
undetectable hCG, <2 mIU/ml. Clearly, to make a close to absolute
detection of pregnancy in women aged 18-40, the serum hCG must be >5
mIU/ml.
Some application for hCG testing, such
as monitoring gestational trophoblastic diseases require more sensitive
hCG detection (6). These are applications looking for recurrence or
persistence of disease in those with proven history of gestational
trophoblastic disease. With this consideration, many manufacturer’s hCG
tests report results as low as 1 mIU/ml. Considering these important
findings, it is critical that all reported hCG results note that using
values of <5 mIU/ml to diagnose pregnancy is just an indication with a
significant false positive rate.
A recent study examines in large groups (n=240) the raised hCG
results observed in peri-menopausal (age 41-55) and post-menopausal (>55
years) women. As found (1), hCG results can be as high as 7.7 mIU/ml in
the peri-menopause group, and 13.1 mIU/ml in the post-menopause groups.
The 97.5th centiles for the viable, peri- and post-menopause
group were 2.5, 4.8 and 7.7 mIU/ml, respectively. It is appropriately
suggested, that when low levels of hCG are detected in peri-menopausal
women, that FSH testing be performed to determine whether patient is in
menopause.
In cases in which persistent low hCG
results are detected malignancies may be considered (6). Trophoblastic
malignancies make intact hCG dimer while other malignancies primarily
produce the hCG free ß-subunit (6, 13, 14). Both are detected by modern
intact hCG assays. Pituitary production of hCG, or extreme cases of
background hCG need to always be considered (1, 6), especially in cases
that are peri-menopause or post-menopause. Pituitary hCG production can
easily be excluded by showing that the hCG production is suppressed by
treatment 3 weeks with a high progesterone oral contraceptive pill
(4,6).
The USA hCG Reference Service aids
physicians with cases having idiopathic hCG production, or hCG
production that does not relate to clinical observations (6). We consult
approximately five or six times each year on cases that turn out to be
pituitary hCG (6). Several of the cases we consult on have already
received needless therapy for an assumed malignancy. We have consulted
so far on 21 cases diagnosed after referral as pituitary hCG, 3 had
needless therapy for assumed cancer, and 2 for assumed recurrence of
gestational trophoblastic disease. The USA hCG Reference Service
requests follow-up information on all cases. In all these 21 cases,
suppression by treatment with a high progesterone oral contraceptive
pill was recommended. In 13 cases feedback was received. In 13 cases the
pill completely suppressed and in 1 cases the pill partially suppressed
hCG production. Of the 21 cases, 11 were peri-menopause and 10 were
post-menopause based upon the age criterion published by Snyder et al
(1). Of the peri-menopause group, hCG ranged from 1.2 - 11.4 mIU/ml, and
of the post-menopause group, from 3.5 - 20 mIU/ml. It is inferred that
most of these cases came within the extremes or 95th centile
of ranges reported here by Snyder et al (1). The USA hCG
Reference Service data very much supports the findings and the concerns
of Snyder et al (1), and supports the use of hormone replacement
therapy to suppress pitruitary production and confirm a pituitary
origin.
The recent publication by Snyder et
al. (1), is a landmark in finally confirming 5 mIU/ml cut-off
for pregnancy. Importantly, they confine it to women 18 - 40 years old.
As demonstrated by Snyder et al. (1) and confirmed by the USA hCG
Reference Service experience, it is important for laboratory manager and
physicians to realize that background hCG becomes naturally raised in
peri- and post-menopause women. This is due to pituitary production.
Pituitary hCG need to be excluded before women are inadvertently treated
for malignancy. IN THE USA hCG REFERENCE SERVICE EXPERIENCE, AN
INCREASING NUMBER OF REFERRALS ARE SIMPLY EXPLAINED BY THE PRESENCE OF
PITUITARY hCG, PRE- OR POST-MENOPAUSE. Warnings on test reports need to
clearly state the 5 mIU/ml cut-off for pregnancy and the potential
inaccuracies of interpreting lower hCG results as indicators of
pregnancy. There is also an important need to note on all reports that
higher background hCG may be observed (maybe >20 mIU/ml) in women over
40 years old, due to increased pituitary hCG production. Laboratory
managers need to be able to advise clinicians on the interpretation of
unexplainable positive hCG results.
1. Snyder JA, Haymond S, Parvin CA,
Gronowski AM, Grenache DG. Diagnostic considerations in the measurement
of human chorionic gonmadotropin in aging women. Clin Chem
2005,
51:1830-35.
2. Alfhan H, Haglund C, Dabek J, Stenman
UH. Concentration of human chorionic gonadotropin, its beta subunit, and
the core fragment of the beta-subunit in serum or urine of men and
non-pregnant women. Clin Chem 1992;38:1981-87.
3. Odel WD, Griffin J. Pulsatile
secretion of human chorionic gonadotropin in normal adults. N Engl J Med
1987:317:1688-91.
4. Stenman UH, Alfhan H, Ranta T,
Vartiainen E, Jalkanen J, Seppala M. Serum levels of human chorionic
gronadotropin in non-pregnant women and men are modulated by
gonadotropin-releasing hormone and sex steroids. J Clin Endocrinol Metab
1987;64:730-36.
5. Borkowski A, Puttaert V, Gyling M,
Muquardt C, Body JJ. Human chorionic gonadotrophn-like substance in
plasma of normal nonpregnant subjects and women with breat cancer. J
Clin Endocrinol Metab 1984;58:1171-78.
6. Cole LA, Khanlian SA. Inappropriate
management of women with persistent low hCG results. J Reprod Med
2004;49:423-32.
7. Hoermann R, Spoettl G, Moncayo R,
Mann K. Evidence for the presence of human chorionic gonadotropin (hCG)
and free beta-subunit of hCG in the human pituitary. J Clin Endocrinol
Metab 1990;71:179-86.
8. Birken S, Maydelman Y, Gawinowicz MA,
Pound A, Liu Y, Hartree AS. Isolation and characterization of human
pituitary chorionic gonadotropin. Endocrinol 1996;137:1402-11.
9. Hoermann R, Spoettl G, Berger P, Mann
K. Immunoreactive human chorionic gonadotropin beta core fragment in
human pituitary. Exper Clin Endocrinol Diabetes 1995;103:324-31.
10. Chen HC, Hodgen GD, Matsuura S, Lin
LJ, Gross E, Reichert LE Jr, Birken S, Canfield RE, Ross GT. Evidence
for a gonadotropin from nonpregnant subjects that has physical,
immunological, and biological similarities to human chorionic
gonadotropin. Proc Natl Acad Sci USA 1976; 23;2885-89.
11. Hartree AS. Shownkeen RC. Stevens
VC. Matsuura S. Ohashi M. Chen HC. Studies of the human chorionic
gonadotrophin-like substance of human pituitary glands and its
significance. Journal of Endocrinology. 1983;96:115-26.
12. Pittaway DE and
Wentz AC. Evaluation of early pregnancy by serial chorionic
gonadotropin determinations: A comparison of methods by receiver
operating characteristic curve analysis.
Fertil Steril 1985; 43: 529-533.
13. Marcillac I,
Toalen F, Bidart J-M, Ghillani P, Ribrag V, Escudier B, Malassagne B,
Droz J-P, Lhommé C, Rougier P, Duvillard P, Prade M, Lugagne P-M,
Richard F, Poynard T, Bohuon C, Wands J, Bellet D. Free human chorionic
gonadotropin
b-subunit
in gonadal and nongonadal neoplasms. Cancer Res. 1992;52:3901-3907.