The corpus luteum is an endocrine gland whose limited lifespan is hormonally programmed. This debate article summarizes findings of our research group that challenge the principle that the end of function of the corpus luteum or luteal regression, once triggered, cannot be reversed. Overturning luteal regression by pharmacological manipulations may be of critical significance in designing strategies to improve fertility efficacy

AA Goyeneche

AJ Zeleznik

B Hinney

C Morales

C Stocco

Carlos M Telleria

CM Telleria

CO Stocco

D Schams

DD Baird

DG Carrizo

G Gibori

GD Niswender

JA McCracken

JM Bowen-Shauver

JS Davis

LK Christenson

MS Smith

N Gleicher

R Webb

TJ Acosta

W Wuttke

WC Duncan

WK Morishige

English

PubMed

Springer - Publisher Connector

BioMed Central
Reproductive Biology and 
Endocrinology
ssOpen AcceDebate
Can luteal regression be reversed?
Carlos M Telleria*
Address: Division of Basic Biomedical Sciences, Sanford School of Medicine of The University of South Dakota, Vermillion, SD 57069, USA
Email: Carlos M Telleria* - carlos.telleria@usd.edu
* Corresponding author    
Abstract
The corpus luteum is an endocrine gland whose limited lifespan is hormonally programmed. This
debate article summarizes findings of our research group that challenge the principle that the end
of function of the corpus luteum or luteal regression, once triggered, cannot be reversed.
Overturning luteal regression by pharmacological manipulations may be of critical significance in
designing strategies to improve fertility efficacy.
Background
The corpus luteum is a peculiar endocrine gland owing to
its limited functional life. How long this gland lives and
when it dies is dictated by a synchronized interplay of hor-
monally regulated events. It undergoes a complex process
of formation or luteinization, which is followed by a
period of active function that is mostly focused on the
production of progesterone. Finally, the gland undergoes
a process of regression associated with the decline in pro-
gesterone output and the demise of the tissue as a conse-
quence of the programmed death of the luteal cells. A
number of excellent review articles have been published
in the last 6–7 years compiling the knowledge mastered
on the molecular regulation of the formation, function
and regression of the corpus luteum [1-13]. Yet, although
luteal regression has been intensively studied, many of the
regulatory mechanisms involved in loss of function and
involution of the luteal structure are not completely
understood. One fundamental question that remains
without an answer is whether the process of luteal regres-
sion, once initiated, can be blocked or even reversed. In
other words, can luteal function be rescued when it has
already been impaired? Or instead, is luteal regression an
irreversible event that cannot be modified when it
progresses beyond a particular molecular step?
Discussion
It is known that a cycling corpus luteum can survive
longer if it is rescued by luteotropins. Physiologically this
rescue takes place when the gland is fully functioning. For
example in humans, chorionic gonadotropin produced by
the trophoblast cells targets and rescues the corpus luteum
at the mid-luteal phase of the menstrual cycle when the
gland is at the maximal steroidogenic output attainable
during non-pregnant cycles [8,14]. In the rat, vaginal stim-
ulation during coitus triggers a neuroendocrine reflex that
leads to the secretion of pituitary prolactin in a pattern of
two daily surges. Prolactin then targets and rescues the
corpus luteum in the morning of diestrus day 2 of the
estrous cycle, when the capacity of the gland to produce
progesterone is also maximal [15]. It is not known, how-
ever, whether the corpus luteum can be rescued while it is
already in regression, and, consequently, not fully func-
tional. Because luteal regression involves a complex and
likely synchronized sequence of molecular events, it is
rather difficult to determine when a pharmacological
intervention could be made to rescue the corpus luteum
making it fully functional again, or, in other words,
"bringing it back to life."
Published: 30 October 2006
Reproductive Biology and Endocrinology 2006, 4:53 doi:10.1186/1477-7827-4-53
Received: 07 September 2006
Accepted: 30 October 2006
This article is available from: http://www.rbej.com/content/4/1/53
© 2006 Telleria; licensee BioMed Central Ltd. 
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), 
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 4
(page number not for citation purposes)
Reproductive Biology and Endocrinology 2006, 4:53 http://www.rbej.com/content/4/1/53In a model of luteal regression induced by the intraovar-
ian administration of luteinizing hormone to day 19 preg-
nant rats, luteal regression was documented 24 hours later
by the decreased activity of the luteal 3beta-hydroxyster-
oid dehydrogenase (3beta-HSD) enzyme (a marker of
reduced steroidogenic output), the decreased intraluteal
concentration of progesterone, and the reduced levels of
progesterone in the circulation [16]. Forty eight hours
after the treatment with luteinizing hormone the process
of luteal regression was further highlighted by increased
luteal activity of the enzyme 20alpha-hydroxysteroid
dehydrogenase -20alpha-HSD, a marker of ongoing pro-
gesterone catabolism in rodents – and increased concen-
tration of prostaglandin F2alpha (PGF2alpha) within the
corpus luteum [16]. However, when progesterone was
administered into the ovarian bursa 24 hours after the
administration of luteinizing hormone -i.e. at a time
when some of the signs of luteal regression had been
already noticeable – the induction of luteal 20alpha-HSD
activity was significantly blocked, serum progesterone
concentration was significantly increased and intraluteal
PGF2alpha concentration was significantly reduced [16].
In another example in which administration of the anti-
progesterone mifepristone (popularly known as RU486)
to day 18 pregnant rats resulted in premature parturition
and signs of luteal regression, administration of andro-
gens (androstenedione or testosterone) 24 hours later sig-
nificantly prevented the declines in corpus luteum weight
and serum progesterone concentration otherwise induced
by the antigestagen [17]. Together all previous evidence
suggest that even though luteal regression was occurring
by the time the tropic hormonal support was given, the
luteotropic hormones were still capable of deregulating
some of the components of the luteal regression program.
Because androstenedione is the main circulating andro-
gen in pregnant rats [18] and progesterone is the major
steroid produced within the corpus luteum [6], one can
speculate that these steroids may be responsible for pro-
tecting luteal cells from undergoing programmed death
during most of the pregnancy. Consequently, as both pro-
gesterone and androstenedione decline at the time of par-
turition in this species, such lack of tropic hormonal
support may trigger luteal regression. However, we have
generated evidence that suggests that if a pharmacological
intervention is made and androstenedione or progester-
one becomes elevated at the proper time, luteal regression
can be prevented. We have shown that increasing intrao-
varian levels of progesterone in late pregnant rats leads to
the interference with PGF2alpha-induced 20alpha-HSD
expression within the corpus luteum [19]. Moreover, by
increasing the levels of circulating progesterone or andros-
tenedione in rats after parturition (i.e. at a time when the
luteal regression process is further more advanced when
compared with that at the end of pregnancy), either phar-
macologically by injecting the hormones [20,21], or phys-
iologically by allowing the animals to lactate [22],
apoptotic programmed death of the luteal cells could be
significantly delayed as assessed by in situ 3' end DNA
labeling and fragmentation of the DNA. This evidence
suggests that the gland, even during regression, maintains
a certain level of function in order to be rescued by an
appropriate stimulus. In support of this hypothesis our
recent data also show an increased expression of receptors
for prolactin (main tropic hormone for the pregnant rat
corpus luteum) and androgen in postpartum rat corpus
luteum, after being temporally down-regulated at the end
of pregnancy [20,22].
Another example supporting the hypothesis that the cor-
pus luteum maintains its capacity to be programmed back
to its main role, even while regressing, came from the
observation that there was always a larger response to
androstenedione, in terms of progesterone producing
capacity, from the luteal cells that were obtained from ani-
mals whose corpora lutea were not at their peaks of func-
tion in vivo. Thus, the addition of androstenedione to the
culture media of luteal cells isolated from animals sacri-
ficed on days 4, 9, 15, or 19 of pregnancy increased pro-
gesterone production over basal levels by 243, 39, 84 and
146%, respectively [23] – notice that in rats ovarian pro-
gesterone production peaks in between days 9 and 15 of
pregnancy, on day 4 is relatively low yet raising, whereas
on day 19 it is already declining [24]. We have also shown
that androstenedione increased progesterone production
by 99, 136, and 277% when added to cultured luteal cells
obtained from animals sacrificed late in pregnancy on
days 19, 20, and 21 respectively [17]. Again, these results
clearly indicate that the maximal steroidogenic response
to androstenedione was obtained from cells that were iso-
lated from corpora lutea taken from day 21 pregnant rats;
this is a time in pregnancy that is associated with the ini-
tiation of luteal regression as marked by the reduced pro-
gesterone output, when compared to that of days 20 and
19 of pregnancy. Altogether these studies suggest that
although the luteal cells were apparently declining their
progesterone output in vivo they still possess an intact
progesterone-producing capacity that was manifested
when they were taken away from the in vivo environment.
From the analysis of these previous studies it is appealing
to hypothesize that whereas the life of the corpus luteum
appears to be "programmed" it may be able to be "repro-
grammed" by a timely pharmacological intervention (Fig-
ure 1). This could be particularly helpful in humans where
corpus luteum deficiency is usually circumvented by the
administration of exogenous progesterone, a strategy that
is not always successful in generating a secretory uterus to
carry out a successful pregnancy until the ovarian/placen-
tal shift of progesterone production takes place [25-27].
By providing only progesterone, the potential effect ofPage 2 of 4
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Reproductive Biology and Endocrinology 2006, 4:53 http://www.rbej.com/content/4/1/53
Page 3 of 4
(page number not for citation purposes)
Schematic representation of the functional reprogramming of regressing corpora luteaFigure 1
Schematic representation of the functional reprogramming of regressing corpora lutea. Support for this model 
comes from studies in rats, in which the corpus luteum (CL) can be rescued or "reprogrammed" while already regressing by 
the action of androstenedione or progesterone. Which factors/hormones/drugs can function as rescuers of regressing corpora 
lutea in other mammalian species, needs to be investigated.
Reproductive Biology and Endocrinology 2006, 4:53 http://www.rbej.com/content/4/1/53other factor/s being produced by the corpus luteum of
early pregnancy that might contribute to implantation
and early fetal development is discouraged. In this context
of reasoning a better therapeutic strategy in patients with
luteal dysfunction could be rescuing the full synthetic
capacity of the corpus luteum of early pregnancy, rather
than providing progesterone replacement. Consequently,
based on the studies conducted in rodents, it seems that
any pharmacological intervention capable of reprogram-
ming this poorly functional corpus luteum associated
with luteal dysfunction appears promising.
Conclusion
Taken together, these previous studies conducted in rats
and mostly generated using two luteotropic agents for this
species, androstenedione and progesterone, strongly sug-
gest that luteal regression can be interfered when it is
already induced, by targeting at least two different steps in
the process: i) rescuing the capacity of the gland to pro-
duce progesterone; and ii) interfering with programmed
death of the luteal cells leading to a delay in the loss of
luteal weight. When showing signs of poor efficiency in its
steroidogenic output, if the corpus luteum could be hor-
monally reprogrammed to prolong its lifespan by pre-
venting its demise, such achievement would be critical in
designing new strategies to improve fertility efficacy.
Acknowledgements
The author is very grateful to Dr. Barbara Goodman for the critical reading 
of the manuscript. This publication was made possible by NIH Grant 
Number 2 P20 RR016479 from the INBRE Program of the National Center 
for Research Resources.
References
1. Christenson LK, Devoto L: Cholesterol transport and steroido-
genesis by the corpus luteum.  Reprod Biol Endocrinol 2003,
1(1):90.
2. Davis JS, Rueda BR: The corpus luteum: an ovarian structure
with maternal instincts and suicidal tendencies.  Front Biosci
2002, 7:d1949-1978.
3. Niswender GD, Juengel JL, Silva PJ, Rollyson MK, McIntush EW:
Mechanisms controlling the function and life span of the cor-
pus luteum.  Physiol Rev 2000, 80(1):1-29.
4. Niswender GD: Molecular control of luteal secretion of pro-
gesterone.  Reproduction 2002, 123(3):333-339.
5. Webb R, Woad KJ, Armstrong DG: Corpus luteum (CL) func-
tion: local control mechanisms.  Domest Anim Endocrinol 2002,
23(1-2):277-285.
6. Bowen-Shauver JM, Gibori G: The corpus luteum of pregnancy.
In The Ovary Edited by: Leung PCK, Adashi EY. San Diego , Elsevier
Academic Press; 2003:201-230. 
7. Acosta TJ, Miyamoto A: Vascular control of ovarian function:
ovulation, corpus luteum formation and regression.  Anim
Reprod Sci 2004, 82-83:127-140.
8. Duncan WC: The human corpus luteum: remodelling during
luteolysis and maternal recognition of pregnancy.  Rev Reprod
2000, 5(1):12-17.
9. Zeleznik AJ, Somers JP: Regulation of the Primate Corpus
Luteum: Cellular and Molecular Perspectives.  Trends Endocri-
nol Metab 1999, 10(5):189-193.
10. McCracken JA, Custer EE, Lamsa JC,  : Luteolysis: a neuroendo-
crine-mediated event.  Physiol Rev 1999, 79(2):263-323.
11. Schams D, Berisha B: Regulation of corpus luteum function in
cattle--an overview.  Reproduction in domestic animals = Zuchthy-
giene 2004, 39(4):241-251.
12. Morales C, Garcia-Pardo L, Reymundo C, Bellido C, Sanchez-Criado
JE, Gaytan F: Different patterns of structural luteolysis in the
human corpus luteum of menstruation.  Hum Reprod 2000,
15(10):2119-2128.
13. Stocco C, Telleria C, Gibori G: Molecular control of corpus
luteum formation, function and regression.  Endocrine Reviews
2007 in press.
14. Baird DD, Weinberg CR, McConnaughey DR, Wilcox AJ: Rescue of
the corpus luteum in human pregnancy.  Biol Reprod 2003,
68(2):448-456.
15. Smith MS, Freeman ME, Neill JD: The control of progesterone
secretion during the estrous cycle and early pseudopreg-
nancy in the rat: prolactin, gonadotropin and steroid levels
associated with rescue of the corpus luteum of pseudopreg-
nancy.  Endocrinology 1975, 96(1):219-226.
16. Stocco CO, Deis RP: Participation of intraluteal progesterone
and prostaglandin F2 alpha in LH-induced luteolysis in preg-
nant rat.  J Endocrinol 1998, 156(2):253-259.
17. Telleria CM, Stocco CO, Stati AO, Rastrilla AM, Carrizo DG, Aguado
LI, Deis RP: Dual regulation of luteal progesterone production
by androstenedione during spontaneous and RU486-induced
luteolysis in pregnant rats.  J Steroid Biochem Mol Biol 1995, 55(3-
4):385-393.
18. Gibori G, Khan I, Warshaw ML, McLean MP, Puryear TK, Nelson S,
Durkee TJ, Azhar S, Steinschneider A, Rao MC: Placental-derived
regulators and the complex control of luteal cell function.
Recent Prog Horm Res 1988, 44:377-429.
19. Telleria CM, Stocco CO, Stati AO, Deis RP: Progesterone recep-
tor is not required for progesterone action in the rat corpus
luteum of pregnancy.  Steroids 1999, 64(11):760-766.
20. Goyeneche AA, Calvo V, Gibori G, Telleria CM: Androstenedione
interferes in luteal regression by inhibiting apoptosis and
stimulating progesterone production.  Biol Reprod 2002,
66(5):1540-7.
21. Goyeneche AA, Deis RP, Gibori G, Telleria CM: Progesterone pro-
motes survival of the rat corpus luteum in the absence of
cognate receptors.  Biol Reprod 2003, 68(1):151-158.
22. Goyeneche AA, Martinez IL, Deis RP, Gibori G, Telleria CM: In vivo
hormonal environment leads to differential susceptibility of
the corpus luteum to apoptosis in vitro.  Biol Reprod 2003,
68(6):2322-2330.
23. Carrizo DG, Rastrilla AM, Telleria CM, Aguado LI: Androstenedi-
one stimulates progesterone production in corpora lutea of
pregnant rats: an effect not mediated by oestrogen.  J Steroid
Biochem Mol Biol 1994, 51(3-4):191-197.
24. Morishige WK, Pepe GJ, Rothchild I: Serum luteinizing hormone,
prolactin and progesterone levels during pregnancy in the
rat.  Endocrinology 1973, 92(5):1527-1530.
25. Hinney B, Henze C, Kuhn W, Wuttke W: The corpus luteum
insufficiency: a multifactorial disease.  J Clin Endocrinol Metab
1996, 81(2):565-570.
26. Wuttke W, Pitzel L, Seidlova-Wuttke D, Hinney B: LH pulses and
the corpus luteum: the luteal phase deficiency LPD).  Vitam
Horm 2001, 63:131-158.
27. Gleicher N, Brown T, Dudkiewicz A, Karande V, Rao R, Balin M,
Campbell D, Pratt D: Estradiol/progesterone substitution in the
luteal phase improves pregnancy rates in stimulated cycles--
but only in younger women.  Early Pregnancy 2000, 4(1):64-73.Page 4 of 4
(page number not for citation purposes)


Can luteal regression be reversed?

Crossref

Abstract The corpus luteum is an endocrine gland whose limited lifespan is hormonally programmed. This debate article summarizes findings of our research group that challenge the principle that the end of function of the corpus luteum or luteal regression, once triggered, cannot be reversed. Overturning luteal regression by pharmacological manipulations may be of critical significance in designing strategies to improve fertility efficacy.</p

Telleria Carlos M

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Reproductive Biology and Endocrinology

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AJ: Rescue of the corpus luteum in human pregnancy. Biol Reprod

Armstrong DG: Corpus luteum (CL) function: local control mechanisms. Domest Anim Endocrinol

Cholesterol transport and steroidogenesis by the corpus luteum. Reprod Biol Endocrinol

CM: Androstenedione interferes in luteal regression by inhibiting apoptosis and stimulating progesterone production. Biol Reprod

CM: In vivo hormonal environment leads to differential susceptibility of the corpus luteum to apoptosis in vitro. Biol Reprod

CM: Progesterone promotes survival of the rat corpus luteum in the absence of cognate receptors. Biol Reprod

Deis RP: Participation of intraluteal progesterone and prostaglandin F2 alpha in LH-induced luteolysis in pregnant rat.

Estradiol/progesterone substitution in the luteal phase improves pregnancy rates in stimulated cycles--but only in younger women. Early Pregnancy

F: Different patterns of structural luteolysis in the human corpus luteum of menstruation. Hum Reprod

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McIntush EW: Mechanisms controlling the function and life span of the corpus luteum. Physiol Rev

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Regulation of corpus luteum function in cattle--an overview. Reproduction in domestic animals = Zuchthygiene

RP: Dual regulation of luteal progesterone production by androstenedione during spontaneous and RU486-induced luteolysis in pregnant rats.

RP: Progesterone receptor is not required for progesterone action in the rat corpus luteum of pregnancy. Steroids

Rueda BR: The corpus luteum: an ovarian structure with maternal instincts and suicidal tendencies. Front Biosci

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Somers JP: Regulation of the Primate Corpus Luteum: Cellular and Molecular Perspectives. Trends Endocrinol Metab

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Can luteal regression be reversed?

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