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

essary to achieve a sufficient biological effect. The

development of galenic formulations allowed proges-
Introduction
terone to be used in hormonal therapies (1). In the
Progesterone allows the endometrial transition from a 1950s, Birch obtained a compound with a progestin
proliferative to the secretory stage, facilitates blastocyst activity that was four to eight times higher than pro-
nesting and is essential to the maintenance of pregnancy. gesterone, replacing the methyl group in position 19
These characteristics explain the ethymology of the hor- with a hydrogen atom (19 nor-progesterone); the for-
mone0 s name, which comes from the Latin pro gesta- mulation of numerous other progestin compounds fol-
tionem. lowed this (2).
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 Key Message
of progesterone in 1933; however, only in the mid- A better understanding of the biological actions of
1940s did Russell Marker begin to synthesize proges- progesterone could enable safe and effective use of
terone from diosgenin, extracted from the Japanese this hormone in different scientific and medical
plant Dioscorea tokoro, and later from Dioscorea mexi- fields.
cana. At first, high concentrations of extract were nec-

8 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 Physiology of progesterone

Methods • the D4-ketosteroid pathway, which leads to the synthe-

sis of 17 a-hydroxyprogesterone and androstenedione,
We searched PubMed up to December 2014 for publica-
and is characteristic of corpus luteum granulosa cells
tions on progesterone/steroidogenesis, with regard to the
(Figure 1).
ovary, endometrium, and non-genomic and genomic
receptor information. 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
Progesterone from cycle to glucocorticoids and androgens (7). Progesterone circulates
pregnancy in the bloodstream bound to cortisol-binding globulin
Steroidogenesis (about 10%) and serum albumin. Progesterone has a rela-
tively short half-life in the body of only five minutes. The
Steroids are ancestral molecules developed about 2 billion metabolites mainly produced in the liver are sulfates and
years ago as primitive bioregulators between primordial glucuronides of reduced derivates and are excreted in the
cells (3). Steroid hormones are characterized by a com- urine. Circulating progesterone is converted to the potent
mon basic structure of cyclopentane-perhydro-phenan- mineralocorticoid desoxycorticosterone (DOC) by renal
trene, a polycyclic complex of 17 carbon atoms forming a 21-hydroxylation. During the luteal phase, during preg-
four-ring system. According to the number of carbon nancy and during exogenous progesterone administration,
atoms, sex steroids are divided into three groups: most circulating DOC arises via this pathway and may
• progestins, characterized by 21-carbon atoms; constitute an unwanted side-effect (7).
• androgens, characterized by 19-carbon atoms;
• estrogens, characterized by 18-carbon atoms. Pharmacokinetics of progesterone
The biosynthetic pathway of steroid hormones is the Although the route of transdermal administration of pro-
same regardless of the steroid-generating organ (ovary, gesterone would offer good patient compliance, it cannot
testis, adrenal cortex, brain and placenta), but the type provide an adequate plasma level of circulating proges-
and the amount of synthesized and secreted steroids terone, and, in addition, the sublingual administration
depends on the expression of enzymes specific to each of route is inconvenient because more daily doses are
these organs. required.
The female gonad, despite being a complete steroido- Orally administered progesterone is absorbed through
genic gland, differs from the other organs of this type in the bowel and reaches the liver via the portal vein, where
enzymatic provision and then in hormones secreted; the it is rapidly converted to metabolites: this is why high
ovaries do not contain 21 a-hydroxylase or 11 a-hydroxy- oral progesterone levels are needed to achieve adequate
lase, so they are not able to produce glucocorticoids or plasma levels.
mineralcorticoids (4). In contrast, the vaginal administration route, even if it
Cholesterol is the common precursor of all steroid hor- does not allow high serum levels to be achieved, has a
mones. Its synthesis starts with the interconversion of two preferential distribution to the uterus and then into the
molecules of acetyl-CoA and proceeds through the forma- endometrium. Although intramuscular administration has
tion of the two intermediate products squalene and lanes- poor patient compliance, it remains the administration
terol (5). Cholesterol conveyed in plasma as low-density route that ensures the achievement of adequate plasma
lipoprotein (LDL) cholesterol (6) interacts with mem- levels that can be monitored by serum level measure-
brane receptors and is internalized in vesicles and then ments. In future, a subcutaneous administration route,
fused with lysosomes. The lysosomal hydrolases allow the which is clearly easier for the patient and thus ensures
intracellular release of free form cholesterol, which is better compliance, may become available.
transported into the mitochondria to be subsequently
converted to pregnenolone. Pregnenolone released from
mitochondria through the action of the cytochrome P450 Role of progesterone in different stages of the
can follow two metabolic pathways: ovarian cycle

• the D5-hydroxy steroid pathway, which leads to the To understand the crucial effect of progesterone on men-
strual cycle physiology, it is necessary to refer briefly to
synthesis of 17 a-hydroxypregnenolone, dehy-
droepiandrosterone (DHEA) and androstenediol, and is the well-known “two-cell-two-gonadotrophin theory”
the main metabolic pathway in adrenal glands and not described for the first time at the end of the 1960s by
luteinized follicle, Ryan and Petro (8).

ª 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015) 8–16 9
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Physiology of progesterone Stefania Taraborrelli

Figure 1. Steroidogenesis, an overview.

The onset of estrogen synthesis in antral and pre- During ovulation, which occurs about 34–36 h after
antral follicles is enabled by the close functional relation the LH surge, the secondary oocyte in metaphase II leaves
between granulosa and theca cells. In fact, through the the dominant follicle and passes into the Fallopian tube
action of luteinizing hormone (LH), theca cells promote lumen, where it can be fertilized. The dominant follicle
the conversion of serum cholesterol to androstenedione, becomes the corpus luteum, a dynamic, atypical and tem-
which is then converted to estrogens by the action of porary endocrine structure. Dominant follicle luteiniza-
follicle-stimulating hormone and by the activity of the tion by LH occurs through the action of angiogenic
enzymatic aromatase system (9). The preovulatory folli- factors contained in follicular fluid (11), which allows the
cle is able to synthesize estrogens as well as progesterone proliferation of blood capillaries and fibroblasts to the
which act directly on granulosa cells by promoting fol- basal lamina of granulosa cells. This mechanism appears
licular growth and by inhibiting apoptotic genes, to be essential to allow LDL cholesterol to reach the lutei-
through interaction with a membrane receptor (Proges- nized cells and then be converted to progesterone
terone Receptor Membrane Component-1, PGRMC1) through the action of cytochrome P450 and a-hydroxy
(10). dehydrogenase (12). In a normal menstrual cycle, proges-

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 Physiology of progesterone

terone concentrations during the follicular phase are defined as the time window in which the blastocyst
lower than 1 ng/mL, but in the days following ovulation adheres to the endometrial cells and then proceeds to
they reach values between 10 and 35 ng/mL. invade the stroma. At the time of conception and in early
In the luteal phase, progesterone secretion is episodic pregnancy, progesterone concentrations do not show sub-
and its variations are closely correlated with the LH pul- stantial changes, but they tend to increase later, reaching
satile release. However, in the early luteal phase the pat- values of 100–300 ng/mL in term pregnancy.
tern of progesterone secretion is stable throughout the Progesterone is almost entirely produced by the corpus
day and is not correlated to LH pulses; conversely, in the luteum until the ninth week of pregnancy (17); thereafter
mid- and late luteal phase the frequency of LH pulses the trophoblasts increase progesterone production, thus
decreases while the amplitude of LH pulse increases. becoming the largest source of this hormone after the
Thus, progesterone levels peak during the mid-luteal 12th week of gestation (18). Corpus luteum deficiency
phase and decline in the late luteal phase (13). In the seems to occur in 35% of recurrent miscarriage cases
absence of conception, the corpus luteum involves rapidly (18). Progesterone is primarily synthetized from maternal
within 9–11 days after ovulation. The mechanism of cor- LDL cholesterol by the placenta through a complete
pus luteum degeneration has not been exactly clarified; enzyme system and only a small fraction comes from fetal
reduced sensitivity to LH and the actions of prostaglan- steroidogenesis. Progesterone affects tubal motility by
dins and cytokines seem to play an important role (13). interacting on specific receptors and acts on endometrial
maturation and on uterine vascularization in the pre-im-
plantation phase (18). Together with human chorionic
Endometrial effects of progesterone during the
gonadotrophin and decidual cortisol it inhibits the T
menstrual cycle
lymphocyte-mediated tissue reaction (18). Progesterone
Progesterone plays a very important role in the transition seems to induce tocolytic and immunosuppressive effects
of the endometrium from the proliferative to the secre- in the areas of major contact between maternal and fetal
tory phase. The expression of endometrial receptors for compartments (18).
estrogens and progesterone changes during the various
phases of the physiological menstrual cycle. During the
Mechanisms of genomic and non-
proliferative phase, there is a predominance of estrogen
genomic action of progesterone
receptors localized in stromal and myometrial epithelial
cells, but during the ovulatory phase this concentration In the last decade, the interest of researchers has focused
falls rapidly due to the suppressive action of progesterone. on the role of progesterone in genomic (nuclear) and
Conversely, progesterone receptors (PRs), mainly local- non-genomic (extranuclear) receptor mechanisms, which
ized in endometrial epithelial cells, increase exponentially cooperate to produce direct effects on cells and tissues.
in the ovulatory phase, as a result of the estradiol action,
and then drastically decrease in the late luteal phase (14).
Genomic receptor mechanism (nuclear)
During the secretory phase, the endometrium is subject
to the combined action of estrogens and progesterone. Progesterone, being a lipophilic molecule, readily crosses
Its0 growth stops with a decline in cellular mitotic activ- cell membranes by diffusion and interacts at the nuclear
ity, mainly due to the action of progesterone. To convert level with the specific PRs, PR-B and PR-A, thus activat-
estradiol to estrone sulfate two enzyme systems are neces- ing about 300 distinct co-regulators that act on riboso-
sary, i.e. 17 a-OH-SD (estradiol dehydrogenase) and sul- mal RNA (19) and result in the production of
fotransferase (15). Moreover, progesterone administration corresponding proteins (20). Nuclear progesterone recep-
during hormonal replacement therapy (HRT) would tors (nPR) take minutes or hours to activate ribosomal
appear to confirm the protective effect of this hormone transcription and are the main regulators of female
on the endometrium of peri- and postmenopausal reproduction (21).
women, as indicated in the Postmenopausal Estrogen/ Genomic receptors PR-B and PR-A (Figure 2) share
Progestin Interventions Study (PEPI trial) (16). 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
Effects of progesterone from the window of
164 amino acids fewer than PR-B (21,22). Under physi-
implantation to pregnancy
ological conditions in humans, cells expressing PR-B
The embryo enters the uterus at the morula stage about and PR-A are equally represented. However, a third iso-
two to three days after fertilization and implantation form of nPR, PR-C, is abundantly found in myometrial
begins five to six days later. Endometrial receptivity is tissue (23).

ª 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015) 8–16 11
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Physiology of progesterone Stefania Taraborrelli

Non-genomic receptor mechanism (extranuclear)

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:
Figure 2. Progesterone receptor (PR) A, B and C structures. (From
Gellersen B, Fernandes MS, Brosens JJ. Non-genomic progesterone • they are too rapid to be compared to the transcrip-
actions in female reproduction. Hum Reprod Update. 2009;15;119– tional effects of the other genomic effects (21);
38. © 2009 European Society of Human Reproduction and • they are found in specific cellular compartments that
Embryology. Reproduced with permission by Oxford University Press lacks cell nuclei such as erythrocytes or platelets (21);
on behalf of the European Society of Human Reproduction and
Embryology).
• 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

2+ +
Acrosome reaction/ Human spermatozoa Ca influx, Cl efflux, cAMP increase Luconi (2004), Blackmore (1991),
capacitation Kirkman-Brown (2000)
Oocyte maturation 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)
Immunoregulatory function Human T-lymphocytes G-protein activation, K+ channel Dosiou (2008), Ehring (1998)
inhibition
Platelet aggregation Human platelets Ca2+ influx Bar (2000), Blackmore (1999, 2008)
Anti-apoptotic effects Rat granulosa cells MAPK kinase (MEK) inhibition, Ca2+ Peluso (2001), Peluso et al. (2004)
homeostasis, Protein kinase G
activation
Muscle contraction Human intestinal smooth Ca2+ currents reduction Bielefeldt (1996)
muscle cells
Vasoreactivity Rat vascular smooth muscle cells Ca2+ influx regulation Barbagallo (2001)
Steroidogenesis and LH Rodent Leydig cells Na+ influx Rossato (1999), El-Hefnawy and
action Huhtaniemi (1998)
Lordosis Female mice Frye (2006)
Transepithelial resistance Human fetal membranes Not assessed Verikouki (2008)
Actin cytoskeleton- Human umbilical vein G-protein activation, PI3 kinase and Fu (2008a, b)
remodeling/cell endothelial cells, human RhoA/ROCK-2 cascade activation
movement breast cancer cells
Neuroprotection Mouse cerebral cortex, rat PI3 kinase activation, ERK1/2 activation, Kaur (2007), Nilsen and Brinton
hippocampal neurons Ca2+ influx inhibition (2003), Cai (2008)
Retinal neuronal activity 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
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Stefania Taraborrelli 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-
Figure 3. Progesterone receptor membrane component 1 (PGRMC1)
agement of osteoporosis and further studies may support
structure. SERBP1: serpinel mRNA binding protein I. (From Gellersen
B, Fernandes MS, Brosens JJ. Non-genomic progesterone actions in its therapeutic benefit in osteoporosis (32).
female reproduction. Hum Reprod Update. 2009;15;119–38. © 2009
European Society of Human Reproduction and Embryology.
Progesterone and the central nervous system
Reproduced with permission by Oxford University Press on behalf of
the European Society of Human Reproduction and Embryology). Progesterone acts on the hypothalamic-pituitary-adreno-
cortical axis by modulating LH secretion, thereby establish-
The progesterone non-genomic receptor localized in ing a feedback mechanism on ovarian steroidogenesis (33).
the cell membrane is called PGRMC1 and has predomi- Progesterone seems to have an inhibitory effect on sexual
nantly been studied in the ovary (Figure 3). The interac- desire (34) in women and it is metabolized in 5a-dihydro-
tion between PGRMC1 and serpinel mRNA binding progesterone and allopregnanolone, the latter compound
protein I (SERBP1) determines the anti-apoptotic effect exerting neuroprotective and restorative effects on trau-
of progesterone on granulosa cells (26). It also seems that matic and ischemic brain injuries (34), where it appears to
PGRMC1, along with SERBP1, is involved in ovarian car- reduce edema and restore the function of the blood barrier.
cinogenesis and its level of expression is potentially asso- Therefore, progesterone must be regarded as a ‘neuros-
ciated with tumor invasion and metastasis (27). Less teroid’ and its metabolite allopregnanolone could also be
information is available on PGRMC2, although its expres- active on glial cells by promoting myelin production and
sion, as well as that of PGRMC1, appears under the con- slowing the progression of Alzheimer’s disease (35). More-
trol of gonadal steroids (27). 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
Progesterone and other target tissues
mice (36). Therefore, progesterone seems to interact with
In addition to its clear effects on reproductive sphere, pro- non-genomic gamma-aminobutyric acid (GABA) receptors
gesterone has multiple functions on various organs and it and, in the future, this agent could be regarded as a thera-
therefore deserves to be considered a “neurosteroid”. 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-
Progesterone and osteoporosis
strual dysphoric disorder (a severe form of premenstrual
Progesterone and synthetic progestins have no or only syndrome).One theory is focused on a “corpus luteum
minor effects on bone. Its derivatives appear to have a lim- insufficiency” which creates a deficiency of progesterone
ited effect on bone density. Progestin receptors have been during this menstrual cycle phase. It has been demonstrated
identified on osteoclasts and osteoblasts (28) and it has a negative effect of low progesterone level on the premen-
been hypothesized that progesterone has a trophic action strual mood symptoms such as aggressive behavior and fati-
on the bone similar to estrogens, inhibiting bone resorp- gue in healthy reproductive age women (37) This might
tion through a direct stimulatory effect on calcitonin secre- explain the improvement of premenstrual syndrome and
tion (29). Progesterone, however, has only minimal effects premenstrual dysphoric disorder symptoms by using pro-
on bone mineral density compared to estradiol, whereas gesterone administration (38).
medroxyprogesterone acetate (MPA) and estradiol induce
a significant decrease of osteoclast activity. These factors
Progesterone and metabolic effects
should be taken into account when choosing progestin for
hormone replacement therapy. The oral combination of 17 Progesterone increases insulin basal levels and promotes
a-estradiol 1 mg/day and low dose norethisterone acetate insulin release after carbohydrate intake (4). The carpal

ª 2015 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 94 (2015) 8–16 13
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Physiology of progesterone Stefania Taraborrelli

tunnel syndrome, which may be caused by diabetic

neuropathy, is usually treated with corticosteroids. Conclusions
Recent studies show that the administration of proges- Based on current findings, progesterone should be rec-
terone after acute back pain or anticancer drug-induced ognized as essential not only in reproductive fields, but
neuropathy (vincristine) (39) could improve neuro- as a potential tool for the management of many clinical
pathic pain by promoting myelin regeneration. More- conditions, including Alzheimer’s disease, cerebral
over, although estrogen therapy is associated with a edema, osteoporosis and diabetic neuropathy. A better
beneficial effect mediated by high-density lipoprotein understanding of the biological genomic and non-ge-
(HDL) increase, the addition of micronized proges- nomic receptor mechanisms could make it possible in
terone to estrogens in HRT has a negative impact on the near future to obtain a more comprehensive knowl-
HDL levels. edge of the safety and efficacy of this agent during hor-
mone replacement therapy (17 a-estradiol and natural
Progesterone and the mammary gland progesterone), with the aim of reducing breast cancer
risk.
During the luteal phase and, to a greater extent, in preg-
nancy, progesterone acts in synergy with estrogens, lead-
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