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OPINION ARTICLE
Progestin potency – Assessment and relevance to choice
of oral contraceptives
Norman Goldstuck
*
Reproduction Research South Africa, 507 St. John’s Rd., Sea Point, Cape Town 8005, South Africa
Received 19 June 2011; accepted 8 August 2011
Available online 8 September 2011
KEYWORDS
Progestin;
Potency;
Oral contraceptive;
Breast cancer;
Ovarian cancer;
Endometrial cancer
Abstract Objectives: To evaluate current information on the potency of older and newer proges-
tins and the relevance to oral contraceptive (OC) use.
Methods: A medline search back to the last review (1985) was conducted.
Results: A thorough review of the pharmacology of the older and newer progestins and their clas-
sification is presented. This is followed by a review of the methods of assessment of progestin
potency in women. Histological as well as newer biochemical methods (nuclear receptors and pla-
cental protein 14) are examined. Progestin potency values for the older and newer progestins are
presented and the reasons for the discrepancies discussed. The delay of menses assay and its prob-
lems with newer formulations is examined including data on current 30–35 lg ethinylestradiol con-
taining OCs. The role of progestin potency in disease causation and prevention, especially in
relation to breast cancer and the protective effects in ovarian and endometrial cancer is reviewed.
The term ‘effective progestin activity’ (EPA) which is dose X potency is defined. The EPA enables
comparisons of differing progestin containing preparations. The terms ‘low dose’ and ‘low potency’
and their historical introduction and implications are discussed. Newer epidemiological studies still
use the old histological data and delay of menses data despite their limited relevance to OCs in pres-
ent use.
*
Tel.: +27 823418200.
E-mail address: nahumzh@yahoo.com
1110-5690 2011 Middle East Fertility Society. Production and
hosting by Elsevier B.V. All rights reserved.
Peer review under responsibility of Middle East Fertility Society.
doi:10.1016/j.mefs.2011.08.006
Production and hosting by Elsevier
Middle East Fertility Society Journal (2011) 16, 248–253
Middle East Fertility Society
Middle East Fertility Society Journal
www.mefsjournal.com
www.sciencedirect.com
Conclusions: Newer progestins are more receptor selective and potency is less relevant than it was
with older progestins. Epidemiological studies of progestin potency and its role in disease generally
use out of date information. There is still confusion about the relationship of dose and potency in
some studies. The use of the EPA can help eliminate this.
2011 Middle East Fertility Society. Production and hosting by Elsevier B.V. All rights reserved.
1. Introduction
The evaluation of synthetic progestogens (progestins) remains
enigmatic. Periodically there is renewed interest in their phar-
macology and clinical actions. This usually corresponds to
periods when new and different progestins become available.
There have been no detailed reviews of progestin potency
and its clinical relevance for at least two decades (1). The pres-
ent review attempts to evaluate all the commonly used proges-
tins in terms of their pharmacology, potency and clinical
action. Conventional classification is used in the main text,
and detailed elaboration of progestin chemistry is presented
in Appendix A.
As their name implies, the function of progestins is to pre-
pare the female body for pregnancy. These effects are exhibited
most obviously in the reproductive tract, but are nevertheless
present throughout the rest of the body. The literature is re-
plete with many clinical and animal studies of many proges-
tins, new and old and of differing chemical composition and
origin. Most progestins have been exhaustively studied
in vitro and in different animal models (2–8). The progestin
binding to various receptors including estrogenic, progesto-
genic, androgenic and mineralocorticoid has been extensively
detailed. For this reason a large array of data on progestin
activity which is often confusing and conflicting has become
available. This review concentrates on human clinical data
and attempts to avoid extrapolating the results from animal
data as a basis for clinical use. This is done commonly, even
in established monographs on oral contraceptive use (9). There
are often profound differences in progestational activity and
potency between human and animal tissues (10,11).
2. Pharmacology of the progestins
The progestins are a chemically diverse group of compounds
with a multiplicity of actions on progestogen as well as estro-
gen, androgen, mineralocorticoid, glucocorticoid and other
receptors. The classification as both older and newer proges-
tins is not ideal and is based on time of introduction (first gen-
eration, second generation and third generation) as well as on
pharmacological distinction Tables 1 and 2. Some authors
have suggested that their classification should be based on bio-
logical properties (12) but this would probably only increase
confusion at this stage.
Progestins differ to a large extent because of their chemical
structure and derivation (13). There are four types of orally ac-
tive progestins. These are 19-nortestosterone (norethindrone)
derivatives, progesterone derivatives, 19 norprogesterone
derivatives (14,15) and one derived from spironolactone (dro-
spirenone) (16,17).
This classification while deficient is the current working
model. A more detailed discussion of the pharmacology of ac-
tion and chemical structures of the older and newer progestins
is found in Appendix A.
3. Determination of progestin potency
Synthetic progestins are compounds which are capable of pro-
ducing a secretory transformation of a proliferative (estrogen
primed) endometrium. Progestin activity and potency are,
therefore, classically evaluated by examining endometrial ef-
fects. These are examined either directly by histological obser-
vation and chemical measurement (18–22) or indirectly by
evaluating menstrual bleeding (23–25).
Pharmacological potency can only be determined for two or
more pharmacologically active compounds when parallel log
dose–response curves (or parallel log dose–response lines)
can be obtained for the drugs being compared (1,26). The rel-
ative potency is determined by the ratio of the doses which are
found to have an equivalent effect. This has been difficult to
achieve at times for all progestin models.
3.1. Histological, morphological and biochemical evaluation
The methods used for the biological evaluation of progestin
potency are summarized in Table 3. A brief historical back-
ground and evaluation of the different methods are considered.
Ferin (1972) compared progestational activity on the endome-
trium in castrated women primed with 50 lg ethinyl estradiol
(EE2). The progestins were given for 5 days after priming
and then a biopsy taken. The comparative potency was deter-
mined by the degree of endometrial glycogen deposition pro-
duced (18). The relative potency of levonorgestrel (LNG)
and norethindrone acetate (NEA) is shown in Table 4.
Table 1 Classification of the earlier progestins.
First generation Second generation Gonanes Third generation Gonanes
Pregnanes Estranes
Chlormadinone acetate Noerethindrone norethindrone acetate Dl-norgestrel Desogestrel
Cyproterone acetate Ethynodiol diacetate Levonorgestrel Norgestimate
Megestrol acetate Lynestranol Gestodene
Norethynodrel
Pregnanes – progesterone derivatives; estranes/gonanes – 19 norethindrone derivatives.
Progestin potency – Assessment and relevance to choice of oral contraceptives 249
Although other progestins were tested, this approach is no
longer used, and will not be considered further.
In her study Grant compared progestational activity of
progestins at different doses combined with mestranol or
EE2 administered from cycle day 5. The days of maximal gly-
cogen deposition into subnuclear vacuoles produced by each
dose of progestational compound were determined by biopsy
at varying times after initiation of the hormone. These results
differ from those of Ferin and are shown in Table 4. The dif-
ferent biopsy times explain why Grant’s results differ from
Ferin’s (20). Surprisingly these studies are still widely quoted
(9) although their findings have been superseded by more
quantitative studies. Both these studies used 50 lg estrogen
as primer and have limited relevance to current oral contracep-
tives, which contain 35 lg or lower doses of estrogen.
King and Whitehead examined endometrial histological
and biochemical changes in response to various progestins in
equine estrogen primed endometrium in postmenopausal wo-
men (21). They calculated progestin effects on epithelial mor-
phological features by summating the appearance of
secretory histologic features, subnuclear glycogen, giant mito-
chondria and the nuclear channel system. They also examined
the effects of progestins on soluble and nuclear estradiol recep-
tors and on isocitric and estradiol dehydrogenases and protein
and deoxyriboncleic acid (DNA) synthesis.
The dose of progestin required to elicit responses similar to
those seen in premenopausal secretory endometrium was as-
sessed for each parameter and the relative potencies calculated.
They found LNG to be eight times more potent than noreth-
indrone (NE) (Table 4).
Byrjalsen and co-workers evaluated the effect of 17b-
estradiol followed by gestodene (GTD) on the postmeno-
pausal endometrium (22). They did this by monitoring the
levels of placental protein 14 (PP14) which is synthesized
in the glandular epithelial cells of the secretory phase endo-
metrium and reflects the secretory activity of the endome-
trium. In their study GTD was 20 times more potent than
NE (Table 4). These studies must be seen as semi-quantita-
tive rather than quantitative as only the biochemical data
gave true dose–response curves.
3.2. Delay of menses
The delay of menses assay attempts to delay menstruation by
administering a progestin with or without an estrogen from
day 20 of a 28-day cycle or from 6 to 7 days after ovulation.
The test dose is given for 20 days and menstruation should
be prevented until 2–3 days after the test dose is discontinued.
The test was introduced by Greenblatt (23,27). The methods
and doses he used were ill defined and he found norgestrel
(NG) to be 30 times more potent than NE (Table 4). Since
NG consists of both the inactive dextronorgestrel as well as
the active levonorgestrel isomers he effectively found levo-
norgestrel to be twice as potent (60 times).
Swyer and Little modified the test in an attempt to make it
quantal (28–31). They gave the test agents to women with reg-
ular cycles from day 20 of the cycle for 20 days. If menstrua-
tion was successfully delayed the test was ‘positive’, if not
‘negative’. By using compounds with a fixed amount of EE2
and varying doses for each progestin studied a 50% effective
dose (ED50) could be found and parallel dose–response curves
could be obtained (31). The results for LNG and norenthind-
rone acetate (NEA) when used in combination with 50 lg EE2
are given in Table 4.
Most oral contraceptives in current usage have between 20
and 35 lg EE2. The importance of the effect of the dose of
EE2 on progestin potency has been emphasized (1,31,32).
Delay of menses assay using 30–35 lg EE2 combinations is
difficult to evaluate using the Swyer test (25). Lower doses of
progestin rarely produced a positive Swyer test. The data were
re-analyzed using the days of delay from the expected date of
onset of the next menstrual period. Log dose versus mean days
of delay gave parallel lines. LNG was found to be 10–12 times
more potent than NE. Preliminary crude estimates for GTD
potency were also obtained (Table 4). Most currently used
contraceptive formulations would probably not produce a po-
sitive Swyer test yet give acceptable bleeding patterns. Any
new delay of menses type studies would have to be designed
and interpreted differently than the classical Greenblatt–Swyer
methodology.
Table 2 Classification of the newer progestins.
19 nor-progesterones Gonanes Estranes Spironolactone
derivative
Promegestone Norelgestromine Dienogest
(non-ethylated)
Drospirenone
Trimegestone Etonogestrel
Demegestone
Nesterone
Nomegestrol acetate
Table 3 Clinical and biological methods of determination of
progestin potency in women.
Method Parameters assessed References
Clinical Delay of menses Greenblatt (23)
Swyer (9)
Goldstuck (25)
Morphological Secretory histology Ferin (18)
Subnuclear glycogen Grant (20)
Giant mitochondria King and
Whitehead (21)
Nuclear channel system
Biochemical Nuclear estradiol receptor Byrjalsen et al. (22)
Isocitric dehydrogenase King and
Whitehead (21)
Estradiol dehydrogenase
DNA synthesis
Secretory endometrial
placental protein 14 (PP14)
250 N. Goldstuck
4. The role of progestin potency in the causation and prevention
of disease
Oral contraceptives (OC) have well-established positive and
negative features (9). The benefits include decreased menstrual
blood loss and decreased dysmenorhea, relief of endometriosis
and protection against ovarian and endometrial cancer. The
drawbacks include increased tendency to venous thromboemo-
bolism and myocardial infarction and stroke possibly due to
lipid and carbohydrate and other metabolic changes (9). Some
attempts have been made to correlate the progestogenic effects
of OCs with the potency of the progestin being used (33).
4.1. Progestin potency and breast cancer
Pike and co-workers published a case control study implying
that the risk of breast cancer was increased in users of high po-
tency progestins (34). They based their potency estimates on
the earlier Greenblatt data. The study was largely discredited
for many reasons. It did, however, result in a renewed interest
in the concept of progestin potency. The role of the combined
estrogen–progestin compounds in the etiology of breast cancer
remains obscure.
4.2. Progestin potency and endometrial cancer
The benefit of combined oral contraceptives in preventing ovar-
ian and endometrial cancer is not in dispute (9). The role of pro-
gestin, and the relative potency in preventing endometrial
cancer has been evaluated in a number of studies (35,36). Voi-
ght et al. and Maxwell et al. used Swyer’s delay of menses data
and Grant and Ferin’s subnucleolar vacuolation tests to quan-
tify progestin potency in their studies (37). Maxwell et al. found
that the potency of progestin in most oral contraceptives was
adequate to provide protection against endometrial cancer
and that higher potency progestins may be more protective
especially in women with a larger body habitus (35). In their
study Voight et al. found that the reduced risk of endometrial
cancer in oral contraceptive users was due to the progestin com-
ponent and that the amount and potency of progestin in most
combined oral contraceptives exceeded the threshold amount
needed to produce this beneficial effect (36,38).
4.3. Progestin potency and ovarian cancer
Lurie et al. (39) and Schildkraut et al. (40) examined the role
of progestin potency in reducing the risk of ovarian cancer.
In both studies the definition of progestin potency was the old-
er Ferin and Grant glycogen vacuolation tests. The two studies
produced conflicting results. The Lurie study found that the
strongest risk reduction for ovarian cancer was associated with
combined oral contraceptives with low-potency progestins
while the Schildkraut study found that the high-potency prog-
estins gave the greatest risk reduction in ovarian cancer.
The central problem with both these studies is that a good
deal of the experience was based on patients using 30 lg EE2
formulations and the potency data which they used was based
on 50 lg EE2 formulation data. Progestin potency is highly
dependent on the concurrent EE2 dose and it would be inter-
esting to see what differences there would be if the progestin
potency calculations were adjusted accordingly (25,32,41,42).
4.4. Progestin potency and metabolic and cardiovascular effects
The effects of combined oral contraceptives on lipid and car-
bohydrate metabolism and in coagulation, venous thrombo-
embolism and arterial diseases have been well studied and
documented (9).
There is no good evidence that progestin potency per se is
significant in these effects. Dorflinger attempted to correlate
the progestin potency with lipid changes in OC users (1). Many
possible factors influence lipid metabolism and the effect of
progestin potency is not quantifiable.
5. The role of progestin potency in choice of oral contraceptive
Goldzieher has highlighted their problem of choosing oral con-
traceptives based on potency alone (26). He also discussed the
problems of extrapolating animal data to humans, and the role
of progestin metabolism as overriding factors (41,42).
Historically the potency issue is an offshoot of the ‘low
dose’ label applied to combined oral contraceptives. The limi-
tations of this label have also been previously examined (25).
Enovid the original birth control pill contained 150 lg mes-
tranol and 10 mg of nonethynodrel. Concurrently with attempts
to lower the amount of hormone required for effective preg-
nancy suppression came the synthesis of newer progestins, a
process which is still unfolding. The use of EE2 as the estrogen
of choice became standard and the dose used has been lowered
to 15 l
g in some instances. The term low dose which makes sense
as far as the estrogen is concerned became confusing for the pro-
gestin content of the OC because of the widely varying doses re-
quired for efficacy. The term ‘low dose’ made no sense for
Table 4 Relative potency of commonly available progestins. Norethindrone = 1.
Method of assessment Progestin Reference
LNG NEA GTD DSG NG DRSP
Endometrial morphology and 4.5
a
4
a
2.5
c
a – Ferin (18); b – Grant (20); c – Wiegratz et al. (13)
Sub-nuclear vacuolation 1.3
b
2
b
Endometrial biochemistry and 8
d
20
e
d – King et al. (21); e – Byrjalsen et al. (22)
Morphology including receptors and PP14
Delay of menses 60
f
2
f
f – Greenblatt (23); g – Swyer (31)
6
g
0.5
g
Delay of menses 12 40 Goldstuck (25)
Delay of menses 10 50 40 20 Runnebaum, Rabe (44)
LNG – levonorgestrel, NEA – norethindrone acetate, GTD – gestodene, DSG – desogestrel, NG – norgestimate, DRSP – drospirenone, The
values for GTD are based on limited amount of data.
Progestin potency – Assessment and relevance to choice of oral contraceptives 251
progestins because on a weight for weight basis some were
clearly more active (‘potent’) than others.
The manufacturers of the progestins which were more ac-
tive and hence required less compound on a weight basis, were
quick to label their product as ‘low dose’. Those who used
more progestin on a weight basis claimed their products were
‘less potent’ and so the controversy began. It becomes obvious
that for a fixed dose of EE2, the amount and potency of the
progestin being used must be taken into consideration. Gold-
stuck has defined the term ‘effective progestin activity’ (EPA)
which is the progestin dose multiplied by the potency (25).
As would be expected when one calculates the EPA’s for the
various OCs there is far less variation than for the dose ranges.
The EPA probably correlates more closely with OC prob-
lems e.g. breakthough bleeding and other side effects of OCs
but this has never been examined in detail. Progestin potency
itself is not, therefore, a factor in the clinical choice of the
OC. Choice of OCs must be made taking into account not only
the dose of estrogen and progestin, but also the various clinical
factors.
6. Conclusions
The significance of progestin potency is losing its relevance, as
newer more receptor targeted progestins are becoming avail-
able. Progestin receptors are ubiquitous in the body. Proges-
tins which stimulate the receptors which lead to inhibition of
ovulation and produce positive endometrial effects with mini-
mal systemic adverse effects (42) and maximal beneficial effects
on metabolism are what are desired. The newer progestins are
beginning to accomplish some of these objectives and as prog-
estins are becoming more specific in stimulating the required
receptors, the dose and potency of progestin required will be
less relevant.
However, in those cases where attempts are made to com-
pare progestins on the basis of potency it would be relevant
to use data which more closely conform to the progestin being
studied.
The use of potency data which are over 25 years old (43)
and which relates to the 50 lg EE2 combinations is not appro-
priate for the 20–35 lg EE2 products which have been avail-
able for around 30 years. The progestin potency data for 20–
30 lg EE2 products are very limited but are available and
should be the basis for potency studies for these progestins
(Table 4). If the amount of progestin in a given OC is to be
compared with a different progestin in another OC in terms
of activity and potency this can be accomplished using the
EPA.
This point was missed by Dorflinger (1) in her review where
she ascribed progestin potency a rating of ‘high’ ‘medium’ and
‘low’ to various formulations (p. 556, Table III). The same
progestin was given a different potency rating in the presence
of the same estrogen because of a different dose. The potency
of a given progestin in the presence of the same amount of
estrogen will always be the same, irrespective of the dose.
The EPA (dose · potency) will of course be different. Studies
comparing the EPA’s of the different progestin effects and side
effects of currently available OCs would be of interest.
This short review compares the chemistry of the older and
newer progestins and attempts to correlate this with biological
and clinical determination of potency where possible. It exam-
ines the role of progestin potency in choosing progestins in
health and disease and the particular relevance to choice of
OCs. An attempt has been made to bring some clarity to what
is sometimes a confusing subject.
Appendix A.
In order to exhibit progestogenic activity a steroid has to
have a 3 keto group and a double bond between C4 and C5 in
ring A (D 4–3-keto group).
Those progestins which lack this are prodrugs and are con-
verted after oral administration into this form e.g. desorgestrel
or norgestimate. These prodrugs are not active parenterally
and their active metabolites etongestrel or norelgestromin
must be used in the vaginal ring or hormonal patch, for
instance.
Pregnanes are progesterone derivatives with absence of a
methyl group at C6. The 19 norprogesterone derivatives differ
from the progesterone derived pregnanes by the absence of a
methyl radical at C-19.
Estranes and gonanes are 19-nortestosterone derivatives.
Estranes have no methyl group between ring A and B and have
an ethinyl group in position 17a. Gonanes also have an ab-
sence of a methyl group between rings A and B and an ethinyl
group in position 17a they also have an ethyl group in position
13. Drospirenone is a spironolactone derivative.
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