A C TA Obstetricia et Gynecologica

AOGS RE V I EW AR TIC LE

Physiology, production and action of progesterone

STEFANIA TARABORRELLI, MD
Reproductive Medicine Unit, GynePro Medical Group, Bologna, Italy

Key words Abstract

Progesterone synthesis, progesterone effects,
window of implantation, genomic and non-
genomic action
Correspondence
Stefania Taraborrelli, GynePro Medical Group,
Via T. Cremona 8, 40137 Bologna, Italy.
E-mail: s.taraborrelli@gynepro.it
Conflict of interest
The author has stated explicitly that there are
no conflicts of interest in connection with this
article.
Please cite this article as: Taraborrelli S.
Physiology, production and action of
progesterone. Acta Obstet Gynecol Scand
2015; 94: 8–16.
Received: 17 March 2015
Accepted: 3 September 2015
DOI: 10.1111/aogs.12771
Introduction. The aim of this article is to review the physiology of proges-
terone and focus on its physiological actions on tissues such as endome-
trium, uterus, mammary gland, cardiovascular system, central nervous
system and bones. In the last decades, the interest of researchers has
focused on the role of progesterone in genomic and non-genomic receptor
mechanisms. Materials and Methods. We searched PubMed up to December
2014 for publications on progesterone/steroidogenesis. Results and Conclu-
sions. A better understanding of the biological genomic and non-genomic
receptor mechanisms could enable us in the near future to obtain a more
comprehensive knowledge of the safety and efficacy of this agent during
hormone replacement therapy (natural progesterone), in vitro fertilization
(water-soluble subcutaneous progesterone), in traumatic brain injury, Alzhei-
mer’s disease and diabetic neuropathy, even though further clinical studies
are needed to prove its usefulness.
Abbreviations: DOC, desoxycorticosterone; FSH, follicle-stimulating hormone;
HDL, high-density lipoprotein; HRT, hormonal replacement therapy; LDL,
low-density lipoprotein; LH, luteinizing hormone; nPR, nuclear progesterone
receptor; PGRMC, progesterone receptor membrane component; PR,
progesterone receptor; SERBP1, serpinel mRNA binding protein I.

essary to achieve a sufficient biological effect. The

Introduction
Progesterone allows the endometrial transition from a
proliferative to the secretory stage, facilitates blastocyst
nesting and is essential to the maintenance of pregnancy.
These characteristics explain the ethymology of the hor-
mone0 s name, which comes from the Latin pro gesta-
tionem.
Progesterone also plays an important role in several
tissues not belonging to the reproductive system, such
as the mammary gland in preparation for breastfeeding,
the cardiovascular system, central nervous system and
bones. Allen originally described the molecular formula
of progesterone in 1933; however, only in the mid-
1940s did Russell Marker begin to synthesize proges-
terone from diosgenin, extracted from the Japanese
plant Dioscorea tokoro, and later from Dioscorea mexi-
cana. At first, high concentrations of extract were nec-
development of galenic formulations allowed proges-
terone to be used in hormonal therapies (1). In the
1950s, Birch obtained a compound with a progestin
activity that was four to eight times higher than pro-
gesterone, replacing the methyl group in position 19
with a hydrogen atom (19 nor-progesterone); the for-
mulation of numerous other progestin compounds fol-
lowed this (2).
Key Message
A better understanding of the biological actions of
progesterone could enable safe and effective use of
this hormone in different scientific and medical
fields.

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Stefania Taraborrelli
Methods
We searched PubMed up to December 2014 for publica-
tions on progesterone/steroidogenesis, with regard to the
ovary, endometrium, and non-genomic and genomic
receptor information.
Progesterone from cycle to
pregnancy
Steroidogenesis
Steroids are ancestral molecules developed about 2 billion
years ago as primitive bioregulators between primordial
cells (3). Steroid hormones are characterized by a com-
mon basic structure of cyclopentane-perhydro-phenan-
trene, a polycyclic complex of 17 carbon atoms forming a
four-ring system. According to the number of carbon
atoms, sex steroids are divided into three groups:
• progestins, characterized by 21-carbon atoms;
• androgens, characterized by 19-carbon atoms;
• estrogens, characterized by 18-carbon atoms.
The biosynthetic pathway of steroid hormones is the
same regardless of the steroid-generating organ (ovary,
testis, adrenal cortex, brain and placenta), but the type
and the amount of synthesized and secreted steroids
depends on the expression of enzymes specific to each of
these organs.
The female gonad, despite being a complete steroido-
genic gland, differs from the other organs of this type in
enzymatic provision and then in hormones secreted; the
ovaries do not contain 21 a-hydroxylase or 11 a-hydroxy-
lase, so they are not able to produce glucocorticoids or
mineralcorticoids (4).
Cholesterol is the common precursor of all steroid hor-
mones. Its synthesis starts with the interconversion of two
molecules of acetyl-CoA and proceeds through the forma-
tion of the two intermediate products squalene and lanes-
terol (5). Cholesterol conveyed in plasma as low-density
lipoprotein (LDL) cholesterol (6) interacts with mem-
brane receptors and is internalized in vesicles and then
fused with lysosomes. The lysosomal hydrolases allow the
intracellular release of free form cholesterol, which is
transported into the mitochondria to be subsequently
converted to pregnenolone. Pregnenolone released from
mitochondria through the action of the cytochrome P450
can follow two metabolic pathways:
• the D5-hydroxy steroid pathway, which leads to the
synthesis of 17 a-hydroxypregnenolone, dehy-
droepiandrosterone (DHEA) and androstenediol, and is
the main metabolic pathway in adrenal glands and not
luteinized follicle,
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Physiology of progesterone
• the D4-ketosteroid pathway, which leads to the synthe-
sis of 17 a-hydroxyprogesterone and androstenedione,
and is characteristic of corpus luteum granulosa cells
(Figure 1).
Whereas progesterone produced from the gonads is car-
ried mostly in the blood to exert its biological function,
progesterone of adrenal origin is largely converted into
glucocorticoids and androgens (7). Progesterone circulates
in the bloodstream bound to cortisol-binding globulin
(about 10%) and serum albumin. Progesterone has a rela-
tively short half-life in the body of only five minutes. The
metabolites mainly produced in the liver are sulfates and
glucuronides of reduced derivates and are excreted in the
urine. Circulating progesterone is converted to the potent
mineralocorticoid desoxycorticosterone (DOC) by renal
21-hydroxylation. During the luteal phase, during preg-
nancy and during exogenous progesterone administration,
most circulating DOC arises via this pathway and may
constitute an unwanted side-effect (7).
Pharmacokinetics of progesterone
Although the route of transdermal administration of pro-
gesterone would offer good patient compliance, it cannot
provide an adequate plasma level of circulating proges-
terone, and, in addition, the sublingual administration
route is inconvenient because more daily doses are
required.
Orally administered progesterone is absorbed through
the bowel and reaches the liver via the portal vein, where
it is rapidly converted to metabolites: this is why high
oral progesterone levels are needed to achieve adequate
plasma levels.
In contrast, the vaginal administration route, even if it
does not allow high serum levels to be achieved, has a
preferential distribution to the uterus and then into the
endometrium. Although intramuscular administration has
poor patient compliance, it remains the administration
route that ensures the achievement of adequate plasma
levels that can be monitored by serum level measure-
ments. In future, a subcutaneous administration route,
which is clearly easier for the patient and thus ensures
better compliance, may become available.
Role of progesterone in different stages of the
ovarian cycle
To understand the crucial effect of progesterone on men-
strual cycle physiology, it is necessary to refer briefly to
the well-known “two-cell-two-gonadotrophin theory”
described for the first time at the end of the 1960s by
Ryan and Petro (8).
9

Physiology of progesterone
Figure 1. Steroidogenesis, an overview.
The onset of estrogen synthesis in antral and pre-
antral follicles is enabled by the close functional relation
between granulosa and theca cells. In fact, through the
action of luteinizing hormone (LH), theca cells promote
the conversion of serum cholesterol to androstenedione,
which is then converted to estrogens by the action of
follicle-stimulating hormone and by the activity of the
enzymatic aromatase system (9). The preovulatory folli-
cle is able to synthesize estrogens as well as progesterone
which act directly on granulosa cells by promoting fol-
licular growth and by inhibiting apoptotic genes,
through interaction with a membrane receptor (Proges-
terone Receptor Membrane Component-1, PGRMC1)
(10).
10 ª 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015) 8–16
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Stefania Taraborrelli
During ovulation, which occurs about 34–36 h after
the LH surge, the secondary oocyte in metaphase II leaves
the dominant follicle and passes into the Fallopian tube
lumen, where it can be fertilized. The dominant follicle
becomes the corpus luteum, a dynamic, atypical and tem-
porary endocrine structure. Dominant follicle luteiniza-
tion by LH occurs through the action of angiogenic
factors contained in follicular fluid (11), which allows the
proliferation of blood capillaries and fibroblasts to the
basal lamina of granulosa cells. This mechanism appears
to be essential to allow LDL cholesterol to reach the lutei-
nized cells and then be converted to progesterone
through the action of cytochrome P450 and a-hydroxy
dehydrogenase (12). In a normal menstrual cycle, proges-

Stefania Taraborrelli
terone concentrations during the follicular phase are
lower than 1 ng/mL, but in the days following ovulation
they reach values between 10 and 35 ng/mL.
In the luteal phase, progesterone secretion is episodic
and its variations are closely correlated with the LH pul-
satile release. However, in the early luteal phase the pat-
tern of progesterone secretion is stable throughout the
day and is not correlated to LH pulses; conversely, in the
mid- and late luteal phase the frequency of LH pulses
decreases while the amplitude of LH pulse increases.
Thus, progesterone levels peak during the mid-luteal
phase and decline in the late luteal phase (13). In the
absence of conception, the corpus luteum involves rapidly
within 9–11 days after ovulation. The mechanism of cor-
pus luteum degeneration has not been exactly clarified;
reduced sensitivity to LH and the actions of prostaglan-
dins and cytokines seem to play an important role (13).
Endometrial effects of progesterone during the
menstrual cycle
Progesterone plays a very important role in the transition
of the endometrium from the proliferative to the secre-
tory phase. The expression of endometrial receptors for
estrogens and progesterone changes during the various
phases of the physiological menstrual cycle. During the
proliferative phase, there is a predominance of estrogen
receptors localized in stromal and myometrial epithelial
cells, but during the ovulatory phase this concentration
falls rapidly due to the suppressive action of progesterone.
Conversely, progesterone receptors (PRs), mainly local-
ized in endometrial epithelial cells, increase exponentially
in the ovulatory phase, as a result of the estradiol action,
and then drastically decrease in the late luteal phase (14).
During the secretory phase, the endometrium is subject
to the combined action of estrogens and progesterone.
Its0 growth stops with a decline in cellular mitotic activ-
ity, mainly due to the action of progesterone. To convert
estradiol to estrone sulfate two enzyme systems are neces-
sary, i.e. 17 a-OH-SD (estradiol dehydrogenase) and sul-
fotransferase (15). Moreover, progesterone administration
during hormonal replacement therapy (HRT) would
appear to confirm the protective effect of this hormone
on the endometrium of peri- and postmenopausal
women, as indicated in the Postmenopausal Estrogen/
Progestin Interventions Study (PEPI trial) (16).
Effects of progesterone from the window of
implantation to pregnancy
The embryo enters the uterus at the morula stage about
two to three days after fertilization and implantation
begins five to six days later. Endometrial receptivity is
ª 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015) 8–16
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Physiology of progesterone
defined as the time window in which the blastocyst
adheres to the endometrial cells and then proceeds to
invade the stroma. At the time of conception and in early
pregnancy, progesterone concentrations do not show sub-
stantial changes, but they tend to increase later, reaching
values of 100–300 ng/mL in term pregnancy.
Progesterone is almost entirely produced by the corpus
luteum until the ninth week of pregnancy (17); thereafter
the trophoblasts increase progesterone production, thus
becoming the largest source of this hormone after the
12th week of gestation (18). Corpus luteum deficiency
seems to occur in 35% of recurrent miscarriage cases
(18). Progesterone is primarily synthetized from maternal
LDL cholesterol by the placenta through a complete
enzyme system and only a small fraction comes from fetal
steroidogenesis. Progesterone affects tubal motility by
interacting on specific receptors and acts on endometrial
maturation and on uterine vascularization in the pre-im-
plantation phase (18). Together with human chorionic
gonadotrophin and decidual cortisol it inhibits the T
lymphocyte-mediated tissue reaction (18). Progesterone
seems to induce tocolytic and immunosuppressive effects
in the areas of major contact between maternal and fetal
compartments (18).
Mechanisms of genomic and non-
genomic action of progesterone
In the last decade, the interest of researchers has focused
on the role of progesterone in genomic (nuclear) and
non-genomic (extranuclear) receptor mechanisms, which
cooperate to produce direct effects on cells and tissues.
Genomic receptor mechanism (nuclear)
Progesterone, being a lipophilic molecule, readily crosses
cell membranes by diffusion and interacts at the nuclear
level with the specific PRs, PR-B and PR-A, thus activat-
ing about 300 distinct co-regulators that act on riboso-
mal RNA (19) and result in the production of
corresponding proteins (20). Nuclear progesterone recep-
tors (nPR) take minutes or hours to activate ribosomal
transcription and are the main regulators of female
reproduction (21).
Genomic receptors PR-B and PR-A (Figure 2) share
the central portion of the DNA binding domain and
the carboxy-terminal end of the ligand binding domain
but they differ in amino acid sequence, PR-A having
164 amino acids fewer than PR-B (21,22). Under physi-
ological conditions in humans, cells expressing PR-B
and PR-A are equally represented. However, a third iso-
form of nPR, PR-C, is abundantly found in myometrial
tissue (23).
11
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Physiology of progesterone Stefania Taraborrelli

Non-genomic receptor mechanism (extranuclear)

Figure 2. Progesterone receptor (PR) A, B and C structures. (From
Gellersen B, Fernandes MS, Brosens JJ. Non-genomic progesterone
actions in female reproduction. Hum Reprod Update. 2009;15;119–
38. © 2009 European Society of Human Reproduction and
Embryology. Reproduced with permission by Oxford University Press
on behalf of the European Society of Human Reproduction and
Embryology).
In 1942, Hans Selye reported that intraperitoneal injection
of progesterone in rats induced a prompt anesthetic effect,
showing for the first time the rapid non-genomic action of
progesterone at tissue level (24). Historically, two models
were studied in a comprehensive way to evaluate proges-
terone non-genomic effects: sperm acrosome reaction and
oocyte maturation induction in animal models such as
Xenopus laevis (25). Over the years, an interesting observa-
tion was made: the rapid effect of the non-genomic pro-
gesterone-R interaction in various tissues activates a wide
variety of secondary messengers (Table 1).
The progesterone non-genomic effects present the fol-
lowing characteristics:
• they are too rapid to be compared to the transcrip-
tional effects of the other genomic effects (21);
• they are found in specific cellular compartments that
lacks cell nuclei such as erythrocytes or platelets (21);
• they are not suppressed by inhibitors of steroid nuclear
receptors (21).

Table 1. Progesterone effects on tissues (from Gellersen B, Fernandes MS, Brosens JJ. Non-genomic progesterone actions in female
reproduction. Hum Reprod Update. 2009;15;119–38. © 2009 European Society of Human Reproduction and Embryology. Reproduced with
permission by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology).*

Physiological action Cell/tissue/organism Signaling pathway References

Acrosome reaction/
capacitation
Oocyte maturation
Immunoregulatory function
Platelet aggregation
Anti-apoptotic effects
Muscle contraction
Vasoreactivity
Steroidogenesis and LH
action
Lordosis
Transepithelial resistance
Actin cytoskeleton-
remodeling/cell
movement
Neuroprotection
Retinal neuronal activity
2+ +
Human spermatozoa Ca influx, Cl efflux, cAMP increase Luconi (2004), Blackmore (1991),
Kirkman-Brown (2000)
Amphibian and fish oocytes G-protein activation and cAMP Zhu et al. (2003b), Thomas et al.
decrease, ERK1/2 activation, PI3 (2002), Maller (2001), Bagowski
kinase activation (2001)
Human T-lymphocytes G-protein activation, K+ channel Dosiou (2008), Ehring (1998)
inhibition
Human platelets Ca2+ influx Bar (2000), Blackmore (1999, 2008)
Rat granulosa cells MAPK kinase (MEK) inhibition, Ca2+ Peluso (2001), Peluso et al. (2004)
homeostasis, Protein kinase G
activation
Human intestinal smooth Ca2+ currents reduction Bielefeldt (1996)
muscle cells
Rat vascular smooth muscle cells Ca2+ influx regulation Barbagallo (2001)
Rodent Leydig cells Na+ influx Rossato (1999), El-Hefnawy and
Huhtaniemi (1998)
Female mice Frye (2006)
Human fetal membranes Not assessed Verikouki (2008)
Human umbilical vein G-protein activation, PI3 kinase and Fu (2008a, b)
endothelial cells, human RhoA/ROCK-2 cascade activation
breast cancer cells
Mouse cerebral cortex, rat PI3 kinase activation, ERK1/2 activation, Kaur (2007), Nilsen and Brinton
hippocampal neurons Ca2+ influx inhibition (2003), Cai (2008)
Mouse rod bipolar cells PI3 kinase activation Koulen (2008)

*
All bibliographic references included in the Table are listed in the References of the article (44–67).

12 ª 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015) 8–16

Stefania Taraborrelli
Figure 3. Progesterone receptor membrane component 1 (PGRMC1)
structure. SERBP1: serpinel mRNA binding protein I. (From Gellersen
B, Fernandes MS, Brosens JJ. Non-genomic progesterone actions in
female reproduction. Hum Reprod Update. 2009;15;119–38. © 2009
European Society of Human Reproduction and Embryology.
Reproduced with permission by Oxford University Press on behalf of
the European Society of Human Reproduction and Embryology).
The progesterone non-genomic receptor localized in
the cell membrane is called PGRMC1 and has predomi-
nantly been studied in the ovary (Figure 3). The interac-
tion between PGRMC1 and serpinel mRNA binding
protein I (SERBP1) determines the anti-apoptotic effect
of progesterone on granulosa cells (26). It also seems that
PGRMC1, along with SERBP1, is involved in ovarian car-
cinogenesis and its level of expression is potentially asso-
ciated with tumor invasion and metastasis (27). Less
information is available on PGRMC2, although its expres-
sion, as well as that of PGRMC1, appears under the con-
trol of gonadal steroids (27).
Progesterone and other target tissues
In addition to its clear effects on reproductive sphere, pro-
gesterone has multiple functions on various organs and it
therefore deserves to be considered a “neurosteroid”.
Progesterone and osteoporosis
Progesterone and synthetic progestins have no or only
minor effects on bone. Its derivatives appear to have a lim-
ited effect on bone density. Progestin receptors have been
identified on osteoclasts and osteoblasts (28) and it has
been hypothesized that progesterone has a trophic action
on the bone similar to estrogens, inhibiting bone resorp-
tion through a direct stimulatory effect on calcitonin secre-
tion (29). Progesterone, however, has only minimal effects
on bone mineral density compared to estradiol, whereas
medroxyprogesterone acetate (MPA) and estradiol induce
a significant decrease of osteoclast activity. These factors
should be taken into account when choosing progestin for
hormone replacement therapy. The oral combination of 17
a-estradiol 1 mg/day and low dose norethisterone acetate
ª 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015) 8–16
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Physiology of progesterone
0.25–0.5 mg/day results in a marked improvement in bone
mineral density in postmenopausal women (30); similarly,
continuous transdermal HRT with 17 a-estradiol 0.05 mg/
day and norethisterone acetate 0.25 mg/day for 14–28 days
shows a clear reduction of bone turnover. Conversely,
micronized progesterone alone in both depot and transder-
mal formulations (31) does not seem to have a positive
biological effect on bone metabolism. Recent studies have
shown that the inhibition of nPRs in rats during the period
of rapid bone growth (1–3 months) increases osteogenesis.
These results seem to suggest a new approach in the man-
agement of osteoporosis and further studies may support
its therapeutic benefit in osteoporosis (32).
Progesterone and the central nervous system
Progesterone acts on the hypothalamic-pituitary-adreno-
cortical axis by modulating LH secretion, thereby establish-
ing a feedback mechanism on ovarian steroidogenesis (33).
Progesterone seems to have an inhibitory effect on sexual
desire (34) in women and it is metabolized in 5a-dihydro-
progesterone and allopregnanolone, the latter compound
exerting neuroprotective and restorative effects on trau-
matic and ischemic brain injuries (34), where it appears to
reduce edema and restore the function of the blood barrier.
Therefore, progesterone must be regarded as a ‘neuros-
teroid’ and its metabolite allopregnanolone could also be
active on glial cells by promoting myelin production and
slowing the progression of Alzheimer’s disease (35). More-
over, progesterone seems to affect the cognitive and behav-
ioral spheres: increased levels of this hormone postpartum
may explain the reduction of aggressive behavior in lactating
mice (36). Therefore, progesterone seems to interact with
non-genomic gamma-aminobutyric acid (GABA) receptors
and, in the future, this agent could be regarded as a thera-
peutic alternative in psychiatric aggressive behavior, depres-
sion and anxiety (36). We report here just a mention on the
progesterone role on premenstrual syndrome and premen-
strual dysphoric disorder (a severe form of premenstrual
syndrome).One theory is focused on a “corpus luteum
insufficiency” which creates a deficiency of progesterone
during this menstrual cycle phase. It has been demonstrated
a negative effect of low progesterone level on the premen-
strual mood symptoms such as aggressive behavior and fati-
gue in healthy reproductive age women (37) This might
explain the improvement of premenstrual syndrome and
premenstrual dysphoric disorder symptoms by using pro-
gesterone administration (38).
Progesterone and metabolic effects
Progesterone increases insulin basal levels and promotes
insulin release after carbohydrate intake (4). The carpal
13

Physiology of progesterone
tunnel syndrome, which may be caused by diabetic
neuropathy, is usually treated with corticosteroids.
Recent studies show that the administration of proges-
terone after acute back pain or anticancer drug-induced
neuropathy (vincristine) (39) could improve neuro-
pathic pain by promoting myelin regeneration. More-
over, although estrogen therapy is associated with a
beneficial effect mediated by high-density lipoprotein
(HDL) increase, the addition of micronized proges-
terone to estrogens in HRT has a negative impact on
HDL levels.
Progesterone and the mammary gland
During the luteal phase and, to a greater extent, in preg-
nancy, progesterone acts in synergy with estrogens, lead-
ing to a down-regulation of estrogen but not progestin
receptors. The mitotic activity of breast epithelial cells is
very high in the follicular phase but slows in the luteal
phase. This finding confirms the protective action of pro-
gesterone on breast tissue due to its inhibitory action on
1 a-hydroxy steroid dehydrogenase and apoptosis (40).
Several studies have been performed to evaluate HRT
safety in postmenopausal women, especially regarding the
risk of developing breast cancer. The Women’s Health
Initiative (WHI) study in 2002 showed an increased,
although not significant, risk of developing breast cancer
after HRT with conjugated estrogens and micronized pro-
gesterone. In 2008, data from the French E3N cohort
study were used to assess and compare the association
between different HRTs and breast cancer risk. During
follow up, 2354 cases of invasive breast cancer occurred
among 80 377 postmenopausal women. In that analysis
the association of estrogen and different progestins in
HRT did not significantly increase breast cancer risk;
however, the association of estrogen-micronized proges-
terone and estrogen-dydrogesterone showed a trend
toward a lower risk (41).
In 2013, the results of the Kronos Early Estrogen
Prevention Study (KEEPS) were published; in addition to
showing the beneficial effect of HRT on the cardiovascu-
lar system and neurocognitive sphere, this study did not
detect a significant increase of breast cancer risk after
HRT with conjugated equine estrogen 0.45 mg/day or
transdermal estradiol 50 lg/day, and micronized proges-
terone (200 mg) administered for 12 days per month
(42).
The REPLENISH trial is a phase 3 randomized placebo
controlled study designed to evaluate the safety of a new
formulation of solubilized 17 a-estradiol and natural
micronized progesterone combined in a single gelatin
capsule opening a safety window between uterine activity
and proliferative mammary gland (43).
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Stefania Taraborrelli
Conclusions
Based on current findings, progesterone should be rec-
ognized as essential not only in reproductive fields, but
as a potential tool for the management of many clinical
conditions, including Alzheimer’s disease, cerebral
edema, osteoporosis and diabetic neuropathy. A better
understanding of the biological genomic and non-ge-
nomic receptor mechanisms could make it possible in
the near future to obtain a more comprehensive knowl-
edge of the safety and efficacy of this agent during hor-
mone replacement therapy (17 a-estradiol and natural
progesterone), with the aim of reducing breast cancer
risk.
References
1. Stefanick ML. Estrogens and progestins: background and
history, trends in use, and guidelines and regimens
approved by the US Food and Drug Administration. Am J
Med. 2005;118:64S–73S.
2. Birch AJ. Hydro aromatic steroid hormones. Part I.
10-Nortestosterone. J Chem. Soc., 1950, 367–368
DOI: 10.1039/JR9500000367.
3. Sandor T, Mehdi AZ. Steroids and evolution. In:
Barrington EJW (ed). Hormones and Evolution. New
York: Academic Press, 1979. pp. 1–72.
4. Genazzani AR (ed). Endocrinologia ginecologica. Editeam,
Cento (FE), Italy. 2004;1–464.
5. Andersen JM, Dietschy JM. Relative importance of high
and low density lipoproteins in the regulation of
cholesterol synthesis in the adrenal gland, ovary and testis
in the rat. J Biol Chem. 1978;253:9024–6.
6. Brown MS, Goldstein JL. Receptor-mediated control of
cholesterol metabolism. Science. 1976;191:150–5.
7. Amadori A, Cavallari C, Giacomucci E, Macrelli S,
Mastronuzzi G, Ucci N. (eds). Fisiologia della
Riproduzione. Bologna: CLUEB, 1994;1–192.
8. Ryan KJ, Petro Z, Kaiser J. Steroid formation by isolated
and recombined granulosa and thecal cells. J Clin
Endocrinol Metab. 1968;28:355–60.
9. Kobayashi M, Nakano R, Ooshima A.
Immunohistochemical localization of pituitary
gonadotropins and gonadal steroids confirms the “two-cell,
two-gonadotrophin” hypothesis of steroidogenesis in the
human ovary. J Endocrinol. 1990;126:483–8.
10. Peluso JJ. Progesterone receptor membrane component 1
and its role in ovarian follicle growth. Front Neurosci.
2013;10:3389–95.
11. Frederick JL, Shimanuki T, diZerega GS. Initiation of
angiogenesis by human follicular fluid. Science.
1984;224:389–90.
12. Revindranath N, Little-Ihrig L, Benyo DF, Zeleznik AJ.
Role of LH in the expression of cholesterol side-chain

Stefania Taraborrelli
cleavage Cit P-450 and 3 a-hydroxy dehydrogenase
isomerase messenger ribonucleic acids in the primate
corpus luteum. Endocrinol. 1992;131:2065–8.
13. Filicori M, Butler JP, Crowley WF Jr. Neuroendocrine
regulation of the corpus luteum in the human. Evidences
for pulsatile gonadotropin secretion. J Clin Endocrinol.
1984;73:1638–47.
14. Lessey BA, Killam AP, Metzger DA, Haney AF, Greene GL,
McCarty KS Jr. Immunohistochemical analysis of human
uterine estrogen and progesterone receptors throughout
the menstrual cycle. J Clin Metabol. 1988;67:334–8.
15. Satyaswaroop PG, Wartell DJ, Mortel R. Distribution of
progesterone receptor, estradiol dehydrogenase and 20
alpha-dihydroprogesterone dehydrogenase activities in
human endometrial glands and stroma: progestin
induction of steroid dehydrogenase activities in vitro is
restricted to the glandular epithelium. Endocrinology.
1982;111:743–9.
16. The Writing Group for the PEPI Trial. Effects of hormone
replacement therapy on endometrial histology in
postmenopausal women. The Postmenopausal Estrogen/
Progestin Interventions (PEPI) Trial. JAMA. 1996;275:370–5.
17. Csapo AL, Pukkinen MO. Effects of luteectomy and
progesterone replacement in early pregnant patients. Am J
Obstet Gynecol. 1973;115:759–64.
18. Schneider MA, Davies MC, Honour JW. The timing of
placental competence in pregnancy after oocyte donation.
Fertil Steril. 1993;59:1059–63.
19. Parker MG, Christian M, White R. The nuclear receptor
co-repressor RIP140 controls the expression of metabolic
gene network. Biochem Soc Trans. 2006;34:1103–6.
20. Lonard DM, Lanz RB, O’Malley BW. Nuclear receptor
coregulators and human disease. Endocr Rev. 2008;28:575–
87.
21. Gellersen B, Fernandes MS, Brosens JJ. Non genomic
progesterone actions in female reproduction. Human
Reprod Update. 2009;15:119–38.
22. Kastner P, Krust A, Turcotte B, Stropp U, Tora L,
Gronemeyer H, et al. Two distinct estrogen-regulated
promoters generate transcripts endcoding the two
functionally different human progesterone receptor forms
A and B. EMBO J. 1990;9:1603–14.
23. Condon JC, Hardy DB, Kovaric K, Mendelson CR. Up-
regulation of the progesterone receptor C isoform in
laboring myometrium by activation of nuclear factor B
may contribute to the onset of labor through inhibition of
PR function. Mol Endocrinol. 2006;20:764–75.
24. Fu X, Simoncini T. Non genomic sex steroid actions in the
vascular system. Semin Reprod Med. 2007;25:178–86.
25. Revelli A. Non genomic actions of steroid hormones in
reproductive tissues. Endocrin Rev. 1998;19:3–17.
26. Peluso JJ, Pappalardo A, Fernandez G, Wu CA.
Involvement of an unnamed protein, RDA288, in the
mechanism through which progesterone mediates its
ª 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015) 8–16
16000412, 2015, S161, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/aogs.12771 by Nat Prov Indonesia, Wiley Online Library on [25/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Physiology of progesterone
antiapoptotic action in spontaneously immortalized
granulosa cells. Endocrinol. 2004;145:3014–22.
27. Koensgen D, Mustea A, Klaman I, Sun P, Zafrakas M,
Lichtenegger W, et al. Expression analysis and RNA
localization of PAI RBP1 (SERBP1) in epithelial ovarian
cancer association with tumor progression. Gynecol Oncol.
2007;107:266–73.
28. Bolvin G, Anthoine-Terrier C, Morel G. Ultrasound of
endogenous hormones and receptors in bone tissue: an
immunocytological approach in frozen sections. Micron.
1994;25:15–27.
29. Greenberg C, Kukreja SC, Bowser EN, Hargis GK, Henderson
WJ, Williams GA. Effects of estradiol and progesterone on
calcitonin secretion. Endocrinology. 1996;118:2594–8.
30. Delmas PD. A combination of low dose of 17 beta
estradiol and norethisterone acetato prevents bone loss and
normalizes bone turnover in postmenopausal women.
Osteoporos Int. 2000;11:177–87.
31. Wren BG. Transdermal progesterone and its effects on
vasomotor symptoms, blood lipid levels, bone metabolic
markers, moods, and quality of life for postmenopausal
women. Menopause. 2003;10:13–8.
32. Yao W, Dai W, Shahnazari M, Pham A, Chen Z, Chen H,
et al. Inhibition of the progesterone nuclear receptor
during the bone linear growth phase increases peak bone
mass in female mice. PLoS ONE. 2010;5:e11410.
33. Goodman RL, Karsch FJ. Pulsatile secretion of LH:
differential suppression by ovarian steroids. Endocrinology.
1980;107:1286–90.
34. Sayeed I. Progesterone is neuroprotective factor in
traumatic and ischemic brain injury. Prog Brain Res.
2009;175:219–37.
35. Wang JM. Regeneration in a degenerating brain: potential
of allopregnagnolone as a neuroregenerative agent. Curr
Alzheimer Res. 2007;4:510–7.
36. Pinna G, Agis-Balboa RC, Pibiri F, Nelson M, Guidotti A,
Costa E. Neurosteroid byosinthesis regulates sexually
dimorphic fear and aggressive behavior in mice.
Neurochem Res. 2008;33:1990–2007.
37. Ziomkiewicz A1, Pawlowski B, Ellison PT, Lipson SF,
Thune I, Jasienska G. Higher luteal progesterone is
associated with low levels of premenstrual aggressive
behavior and fatigue. Biol Psychol. 2012;91:376–82.
38. Kaore SN, Langade DK, Yadav VK, Sharma P, Thawani
VR, Sharma R. Novel actions of progesterone: what we
know today and what will be the scenario in the future? J
Pharm Pharmacol. 2012;64:1040–62.
39. Meyer L, Patte-Mensah C, Taleb O, Mensah-Nyagan AG.
Cellular and functional evidence for a protective action of
neurosteroids against vincristine chemotherapy-induced
painful neuropathy. Cell Mol Life Sci. 2010;67:3017–34.
40. De Lignieres B. Estradiol and progesterone regulate the
proliferation of human breast epithelial cells. Fertil Steril.
1998;69:963–9.
15

Physiology of progesterone
41. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks
for breast cancer associated with different hormone
replacement therapies: results from E3N cohort study.
Breast Cancer Res. 2008;107:103–11.
42. Wharton W, Gleason CE, Miller VM, Asthana S. Rationale
and design of the KEEPS and the KEEPS Cognitive and
affective sub study. Brain Res. 2013;1514:12–7.
43. Mirkin S, Amadio JM, Bernick BA, Pickar JH, Archer DF.
17 b-estradiol and natural progesterone for menopausal
hormone therapy: REPLENISH phase 3 study design of
combination capsule and evidence review. Maturitas.
2015;81:28–35.
44. Luconi M, Francavilla F, Porazzi I, Macerola B, Forti G,
Baldi E. Human spermatozoa as a model for studying
membrane receptors mediating rapid nongenomic effects
of progesterone and estrogens. Steroids. 2004;69:553–9.
45. Blackmore PF, Neulen J, Lattanzio F, Beebe SJ. Cell
surface-binding sites for progesterone mediate calcium
uptake in human sperm. J Biol Chem. 1991;266:18655–9.
46. Kirkman-Brown JC, Bray C, Stewart PM, Barratt CL,
Publicover SJ. Biphasic elevation of [Ca2+]i in individual
human spermatozoa exposed to progesterone. Dev Biol.
2000;222:326–35.
47. Maller JL. The elusive progesterone receptor in Xenopus
oocytes. Proc Natl Acad Sci USA. 2001;98:8–10.
48. Bagowski CP, Myers JW, Ferrell JE Jr. The classical
progesterone receptor associates with p42 MAPK and is
involved in phosphatidylinositol 3-kinase signaling in
Xenopus oocytes. J Biol Chem. 2001;276:37708–14.
49. Dosiou C, Hamilton AE, Pang Y, Overgaard MT, Tulac S,
Dong J, et al. Expression of membrane progesterone
receptors on human T lymphocytes and Jurkat cells and
activation of G-proteins by progesterone. J Endocrinol.
2008;196:67–77.
50. Ehring GR, Kerschbaum HH, Eder C, Neben AL, Fanger
CM, Khoury RM, et al. A nongenomic mechanism for
progesterone-mediated immunosuppression: inhibition of
K+ channels, Ca2+ signaling, and gene expression in T
lymphocytes. J Exp Med. 1998;188:1593–602.
51. Bar J, Lahav J, Hod M, Ben-Rafael Z, Weinberger I,
Brosens J. Regulation of platelet aggregation and adenosine
triphosphate release in vitro by 17b-estradiol and
medroxyprogesterone acetate in postmenopausal women.
Thromb Haemost. 2000;84:695–700.
52. Blackmore PF, Fisher JF, Spilman CH, Bleasdale JE. Unusual
steroid specificity of the cell surface progesterone receptor
on human sperm. Mol Pharmacol. 1996;49:727–39.
53. Blackmore PF. Progesterone metabolites rapidly stimulate
calcium influx in human platelets by a src-dependent
pathway. Steroids. 2008;73:738–50.
54. Peluso JJ, Pappalardo A. Progesterone regulates granulosa
cell viability through a protein kinase G-dependent
mechanism that may involve 14-3-3s. Biol Reprod.
2004;71:1870–8.
16 ª 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015) 8–16
16000412, 2015, S161, Downloaded from https://obgyn.onlinelibrary.wiley.com/doi/10.1111/aogs.12771 by Nat Prov Indonesia, Wiley Online Library on [25/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Stefania Taraborrelli
55. Peluso JJ, Fernandez G, Pappalardo A, White BA.
Characterization of a putative membrane receptor for
progesterone in rat granulosa cells. Biol Reprod.
2001;65:94–101.
56. Bielefeldt K, Waite L, Abboud FM, Conklin JL.
Nongenomic effects of progesterone on human intestinal
smooth muscle cells. Am J Physiol. 1996;271:G370–6.
57. Barbagallo M, Dominguez LJ, Licata G, Shan J, Bing L,
Karpinski E, et al. Vascular effects of progesterone: role of
cellular calcium regulation. Hypertension. 2001;37:142–7.
58. Rossato M, Nogara A, Merico M, Ferlin A, Foresta C.
Identification of functional binding sites for progesterone in
rat Leydig cell plasma membrane. Steroids. 1999;64:168–75.
59. El-Hefnawy T, Huhtaniemi I. Progesterone can participate
in downregulation of the luteinizing hormone receptor
gene expression and function in cultured murine Leydig
cells. Mol Cell Endocrinol. 1998;137:127–38.
60. Frye CA, Sumida K, Lydon JP, O’Malley BW, Pfaff DW.
Mid-aged and aged wild-type and progestin receptor
knockout (PRKO) mice demonstrate rapid progesterone
and 3a,5a-THP-facilitated lordosis. Psychopharmacology.
2006;185:423–32.
61. Verikouki CH, Hatzoglou CH, Gourgoulianis KI,
Molyvdas PA, Kallitsaris A, Messinis IE. Rapid effect of
progesterone on transepithelial resistance of human fetal
membranes: evidence for non-genomic action. Clin Exp
Pharmacol Physiol. 2008;35:174–9.
62. Fu XD, Flamini M, Sanchez AM, Goglia L, Giretti MS,
Genazzani AR, et al. Progestogens regulate endothelial
actin cytoskeleton and cell movement via the actin-binding
protein moesin. Mol Hum Reprod. 2008a;14:225–34.
63. Fu XD, Giretti MS, Baldacci C, Garibaldi S, Flamini M,
Sanchez AM, et al. Extra-nuclear signaling of progesterone
receptor to breast cancer cell movement and invasion
through the actin cytoskeleton. PLoS ONE. 2008b;3:e2790.
64. Kaur P, Jodhka PK, Underwood WA, Bowles CA, de
Fiebre NC, de Fiebre CM, et al. Progesterone increases
brain-derived neuroptrophic factor expression and protects
against glutamate toxicity in a mitogen-activated protein
kinase- and phosphoinositide-3 kinase-dependent manner
in cerebral cortical explants. J Neurosci Res.
2007;85:2441–9.
65. Nilsen J, Brinton RD. Divergent impact of progesterone
and medroxyprogesterone acetate (Provera) on nuclear
mitogenactivated protein kinase signaling. Proc Natl Acad
Sci USA. 2003;100:10506–11.
66. Cai W, Zhu Y, Furuya K, Li Z, Sokabe M, Chen L. Two
different molecular mechanisms underlying progesterone
neuroprotection against ischemic brain damage.
Neuropharmacology. 2008;55:127–38.
67. Koulen P, Madry C, Duncan RS, Hwang JY, Nixon E,
McClung N, et al. Progesterone potentiates IP3-mediated
calcium signaling through Akt/PKB. Cell Physiol Biochem.
2008;21:161–72.