Middle East Fertility Society Journal
Volume 16, Issue 4 , Pages 248-253, December 2011

Progestin potency – Assessment and relevance to choice of oral contraceptives

Reproduction Research South Africa, 507 St. John’s Rd., Sea Point, Cape Town 8005, South Africa

Received 19 June 2011; accepted 8 August 2011.

Article Outline

Abstract 

Objectives

To evaluate current information on the potency of older and newer progestins 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 classification 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 placental 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 problems with newer formulations is examined including data on current 30–35μg ethinylestradiol containing 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 present use.

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 Epidemiological studies of progestin potency and its role in disease generally use out of date information.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.

Keywords: Progestin, Potency, Oral contraceptive, Breast cancer, Ovarian cancer, Endometrial cancer

 

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1. Introduction 

The evaluation of synthetic progestogens (progestins) remains enigmatic. Periodically there is renewed interest in their pharmacology 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 present review attempts to evaluate all the commonly used progestins 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 prepare 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 replete with many clinical and animal studies of many progestins, new and old and of differing chemical composition and origin. Most progestins have been exhaustively studied in vitro and in different animal models (2), (3), (4), (5), (6), (7), (8). The progestin binding to various receptors including estrogenic, progestogenic, 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).

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2. Pharmacology of the progestins 

The progestins are a chemically diverse group of compounds with a multiplicity of actions on progestogen as well as estrogen, androgen, mineralocorticoid, glucocorticoid and other receptors. The classification as both older and newer progestins is not ideal and is based on time of introduction (first generation, second generation and third generation) as well as on pharmacological distinction Table 1, Table 2. Some authors have suggested that their classification should be based on biological properties (12) but this would probably only increase confusion at this stage.

Table 1. Classification of the earlier progestins.
First generationSecond generation GonanesThird generation Gonanes
PregnanesEstranes
Chlormadinone acetateNoerethindrone norethindrone acetateDl-norgestrelDesogestrel
Cyproterone acetateEthynodiol diacetateLevonorgestrelNorgestimate
Megestrol acetateLynestranol Gestodene
Norethynodrel

Pregnanes – progesterone derivatives; estranes/gonanes – 19 norethindrone derivatives.

Table 2. Classification of the newer progestins.
19 nor-progesteronesGonanesEstranesSpironolactone derivative
PromegestoneNorelgestromineDienogest
(non-ethylated)		Drospirenone
TrimegestoneEtonogestrel
Demegestone
Nesterone
Nomegestrol acetate

Progestins differ to a large extent because of their chemical structure and derivation (13). There are four types of orally active progestins. These are 19-nortestosterone (norethindrone) derivatives, progesterone derivatives, 19 norprogesterone derivatives (14), (15) and one derived from spironolactone (drospirenone) (16), (17).

This classification while deficient is the current working model. A more detailed discussion of the pharmacology of action and chemical structures of the older and newer progestins is found in Appendix A.

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3. Determination of progestin potency 

Synthetic progestins are compounds which are capable of producing a secretory transformation of a proliferative (estrogen primed) endometrium. Progestin activity and potency are, therefore, classically evaluated by examining endometrial effects. These are examined either directly by histological observation and chemical measurement (18), (19), (20), (21), (22) or indirectly by evaluating menstrual bleeding (23), (24), (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 relative 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 background and evaluation of the different methods are considered. Ferin (1972) compared progestational activity on the endometrium in castrated women primed with 50μg ethinyl estradiol (EE2). The progestins were given for 5days after priming and then a biopsy taken. The comparative potency was determined by the degree of endometrial glycogen deposition produced (18). The relative potency of levonorgestrel (LNG) and norethindrone acetate (NEA) is shown in Table 4. Although other progestins were tested, this approach is no longer used, and will not be considered further.

Table 3. Clinical and biological methods of determination of progestin potency in women.
MethodParameters assessedReferences
ClinicalDelay of mensesGreenblatt (23)
Swyer (9)
Goldstuck (25)
MorphologicalSecretory histologyFerin (18)
Subnuclear glycogenGrant (20)
Giant mitochondriaKing and Whitehead (21)
Nuclear channel system
BiochemicalNuclear estradiol receptorByrjalsen et al. (22)
Isocitric dehydrogenaseKing and Whitehead (21)
Estradiol dehydrogenase
DNA synthesis
Secretory endometrial placental protein 14 (PP14)
Table 4. Relative potency of commonly available progestins. Norethindrone=1.
Method of assessmentProgestinReference
LNGNEAGTDDSGNGDRSP
Endometrial morphology and4.5a4a 2.5ca – Ferin (18); b – Grant (20); c – Wiegratz et al. (13)
Sub-nuclear vacuolation1.3b2b
Endometrial biochemistry and8d 20e d – King et al. (21); e – Byrjalsen et al. (22)
Morphology including receptors and PP14
Delay of menses60f2f f – Greenblatt (23); g – Swyer (31)
6g0.5g
Delay of menses12 40 Goldstuck (25)
Delay of menses10 504020 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.

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 glycogen 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 different 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 50μg estrogen as primer and have limited relevance to current oral contraceptives, which contain 35μg 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 women (21). They calculated progestin effects on epithelial morphological features by summating the appearance of secretory histologic features, subnuclear glycogen, giant mitochondria and the nuclear channel system. They also examined the effects of progestins on soluble and nuclear estradiol receptors 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 assessed for each parameter and the relative potencies calculated. They found LNG to be eight times more potent than norethindrone (NE) (Table 4).

Byrjalsen and co-workers evaluated the effect of 17β-estradiol followed by gestodene (GTD) on the postmenopausal 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 endometrium and reflects the secretory activity of the endometrium. In their study GTD was 20 times more potent than NE (Table 4). These studies must be seen as semi-quantitative 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 7days after ovulation. The test dose is given for 20days and menstruation should be prevented until 2–3days 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 levonorgestrel to be twice as potent (60 times).

Swyer and Little modified the test in an attempt to make it quantal (28), (29), (30), (31). They gave the test agents to women with regular cycles from day 20 of the cycle for 20days. If menstruation 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 norenthindrone acetate (NEA) when used in combination with 50μg EE2 are given in Table 4.

Most oral contraceptives in current usage have between 20 and 35μg 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 30–35μg 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 positive 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.

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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 thromboemobolism 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 potency 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 ovarian and endometrial cancer is not in dispute (9). The role of progestin, and the relative potency in preventing endometrial cancer has been evaluated in a number of studies (35), (36). Voight et al. and Maxwell et al. used Swyer’s delay of menses data and Grant and Ferin’s subnucleolar vacuolation tests to quantify 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 component 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 older 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 progestins 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 30μg EE2 formulations and the potency data which they used was based on 50μg EE2 formulation data. Progestin potency is highly dependent on the concurrent EE2 dose and it would be interesting 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 carbohydrate metabolism and in coagulation, venous thromboembolism 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.

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5. The role of progestin potency in choice of oral contraceptive 

Goldzieher has highlighted their problem of choosing oral contraceptives 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 limitations of this label have also been previously examined (25).

Enovid the original birth control pill contained 150μg mestranol and 10mg of nonethynodrel. Concurrently with attempts to lower the amount of hormone required for effective pregnancy 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 15μg in some instances. The term low dose which makes sense as far as the estrogen is concerned became confusing for the progestin content of the OC because of the widely varying doses required for efficacy. The term ‘low dose’ made no sense for progestins because on a weight for weight basis some were clearly more active (‘potent’) than others.

The manufacturers of the progestins which were more active 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. Goldstuck 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 problems 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.

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6. Conclusions 

The significance of progestin potency is losing its relevance, as newer more receptor targeted progestins are becoming available. Progestin receptors are ubiquitous in the body. Progestins which stimulate the receptors which lead to inhibition of ovulation and produce positive endometrial effects with minimal 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 progestins 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 compare 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 25years old (43) and which relates to the 50μg EE2 combinations is not appropriate for the 20–35μg EE2 products which have been available for around 30years. The progestin potency data for 20–30μg 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 examines 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.

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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 (Δ 4–3-keto group).

Those progestins which lack this are prodrugs and are converted 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 17α. Gonanes also have an absence of a methyl group between rings A and B and an ethinyl group in position 17α they also have an ethyl group in position 13. Drospirenone is a spironolactone derivative.

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PII: S1110-5690(11)00077-X

doi:10.1016/j.mefs.2011.08.006

Middle East Fertility Society Journal
Volume 16, Issue 4 , Pages 248-253, December 2011

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