Progestin Potency €“ Assessment and Relevance to Choice of Oral

Middle East Fertility Society Journal (2011) 16, 248–253

Middle East Fertility Society Middle East Fertility Society Journal

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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 Abstract Objectives: To evaluate current information on the potency of older and newer proges- Progestin; tins and the relevance to oral contraceptive (OC) use. Potency; Methods: A medline search back to the last review (1985) was conducted. Oral contraceptive; Results: A thorough review of the pharmacology of the older and newer progestins and their clas- Breast cancer; sification is presented. This is followed by a review of the methods of assessment of progestin Ovarian cancer; potency in women. Histological as well as newer biochemical methods (nuclear receptors and pla- Endometrial cancer 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.

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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 Progestin potency – Assessment and relevance to choice of oral contraceptives 249

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 logical properties (12) but this would probably only increase confusion at this stage. The evaluation of synthetic progestogens (progestins) remains Progestins differ to a large extent because of their chemical enigmatic. Periodically there is renewed interest in their phar- structure and derivation (13). There are four types of orally ac- macology and clinical actions. This usually corresponds to tive progestins. These are 19-nortestosterone (norethindrone) periods when new and different progestins become available. derivatives, progesterone derivatives, 19 norprogesterone There have been no detailed reviews of progestin potency derivatives (14,15) and one derived from spironolactone (dro- and its clinical relevance for at least two decades (1). The pres- spirenone) (16,17). ent review attempts to evaluate all the commonly used proges- This classification while deficient is the current working tins in terms of their pharmacology, potency and clinical model. A more detailed discussion of the pharmacology of ac- action. Conventional classification is used in the main text, tion and chemical structures of the older and newer progestins and detailed elaboration of progestin chemistry is presented is found in Appendix A. in Appendix A. As their name implies, the function of progestins is to pre- 3. Determination of progestin potency pare the female body for pregnancy. These effects are exhibited most obviously in the reproductive tract, but are nevertheless Synthetic progestins are compounds which are capable of pro- present throughout the rest of the body. The literature is re- ducing a secretory transformation of a proliferative (estrogen plete with many clinical and animal studies of many proges- primed) endometrium. Progestin activity and potency are, tins, new and old and of differing chemical composition and therefore, classically evaluated by examining endometrial ef- origin. Most progestins have been exhaustively studied fects. These are examined either directly by histological obser- in vitro and in different animal models (2–8). The progestin vation and chemical measurement (18–22) or indirectly by binding to various receptors including estrogenic, progesto- evaluating menstrual bleeding (23–25). genic, androgenic and mineralocorticoid has been extensively Pharmacological potency can only be determined for two or detailed. For this reason a large array of data on progestin more pharmacologically active compounds when parallel log activity which is often confusing and conflicting has become dose–response curves (or parallel log dose–response lines) available. This review concentrates on human clinical data can be obtained for the drugs being compared (1,26). The rel- and attempts to avoid extrapolating the results from animal ative potency is determined by the ratio of the doses which are data as a basis for clinical use. This is done commonly, even found to have an equivalent effect. This has been difficult to in established monographs on oral contraceptive use (9). There achieve at times for all progestin models. are often profound differences in progestational activity and potency between human and animal tissues (10,11). 3.1. Histological, morphological and biochemical evaluation

2. Pharmacology of the progestins The methods used for the biological evaluation of progestin potency are summarized in Table 3. A brief historical back- The progestins are a chemically diverse group of compounds ground and evaluation of the different methods are considered. with a multiplicity of actions on progestogen as well as estro- Ferin (1972) compared progestational activity on the endome- gen, androgen, mineralocorticoid, glucocorticoid and other trium in castrated women primed with 50 lg ethinyl estradiol receptors. The classification as both older and newer proges- (EE2). The progestins were given for 5 days after priming tins is not ideal and is based on time of introduction (first gen- and then a biopsy taken. The comparative potency was deter- eration, second generation and third generation) as well as on mined by the degree of endometrial glycogen deposition pro- pharmacological distinction Tables 1 and 2. Some authors duced (18). The relative potency of levonorgestrel (LNG) have suggested that their classification should be based on bio- 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. 250 N. Goldstuck

Table 2 Classification of the newer progestins. 19 nor-progesterones Gonanes Estranes Spironolactone derivative Promegestone Norelgestromine Dienogest Drospirenone (non-ethylated) Trimegestone Etonogestrel Demegestone Nesterone Nomegestrol acetate

Byrjalsen and co-workers evaluated the effect of 17b- Table 3 Clinical and biological methods of determination of estradiol followed by gestodene (GTD) on the postmeno- progestin potency in women. pausal endometrium (22). They did this by monitoring the Method Parameters assessed References levels of placental protein 14 (PP14) which is synthesized Clinical Delay of menses Greenblatt (23) in the glandular epithelial cells of the secretory phase endo- Swyer (9) metrium and reflects the secretory activity of the endome- Goldstuck (25) trium. In their study GTD was 20 times more potent than Morphological Secretory histology Ferin (18) NE (Table 4). These studies must be seen as semi-quantita- Subnuclear glycogen Grant (20) tive rather than quantitative as only the biochemical data Giant mitochondria King and gave true dose–response curves. Whitehead (21) Nuclear channel system 3.2. Delay of menses Biochemical Nuclear estradiol receptor Byrjalsen et al. (22) Isocitric dehydrogenase King and The delay of menses assay attempts to delay menstruation by Whitehead (21) administering a progestin with or without an estrogen from Estradiol dehydrogenase day 20 of a 28-day cycle or from 6 to 7 days after ovulation. DNA synthesis The test dose is given for 20 days and menstruation should Secretory endometrial placental protein 14 (PP14) 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 Although other progestins were tested, this approach is no (NG) to be 30 times more potent than NE (Table 4). Since longer used, and will not be considered further. NG consists of both the inactive dextronorgestrel as well as In her study Grant compared progestational activity of the active levonorgestrel isomers he effectively found levo- progestins at different doses combined with mestranol or norgestrel to be twice as potent (60 times). EE2 administered from cycle day 5. The days of maximal gly- Swyer and Little modified the test in an attempt to make it cogen deposition into subnuclear vacuoles produced by each quantal (28–31). They gave the test agents to women with reg- dose of progestational compound were determined by biopsy ular cycles from day 20 of the cycle for 20 days. If menstrua- at varying times after initiation of the hormone. These results tion was successfully delayed the test was ‘positive’, if not differ from those of Ferin and are shown in Table 4. The dif- ‘negative’. By using compounds with a fixed amount of EE2 ferent biopsy times explain why Grant’s results differ from and varying doses for each progestin studied a 50% effective Ferin’s (20). Surprisingly these studies are still widely quoted dose (ED50) could be found and parallel dose–response curves (9) although their findings have been superseded by more could be obtained (31). The results for LNG and norenthind- quantitative studies. Both these studies used 50 lg estrogen rone acetate (NEA) when used in combination with 50 lg EE2 as primer and have limited relevance to current oral contracep- are given in Table 4. tives, which contain 35 lg or lower doses of estrogen. Most oral contraceptives in current usage have between 20 King and Whitehead examined endometrial histological and 35 lg EE2. The importance of the effect of the dose of and biochemical changes in response to various progestins in EE2 on progestin potency has been emphasized (1,31,32). equine estrogen primed endometrium in postmenopausal wo- Delay of menses assay using 30–35 lg EE2 combinations is men (21). They calculated progestin effects on epithelial mor- difficult to evaluate using the Swyer test (25). Lower doses of phological features by summating the appearance of progestin rarely produced a positive Swyer test. The data were secretory histologic features, subnuclear glycogen, giant mito- re-analyzed using the days of delay from the expected date of chondria and the nuclear channel system. They also examined onset of the next menstrual period. Log dose versus mean days the effects of progestins on soluble and nuclear estradiol recep- of delay gave parallel lines. LNG was found to be 10–12 times tors and on isocitric and estradiol dehydrogenases and protein more potent than NE. Preliminary crude estimates for GTD and deoxyriboncleic acid (DNA) synthesis. potency were also obtained (Table 4). Most currently used The dose of progestin required to elicit responses similar to contraceptive formulations would probably not produce a po- those seen in premenopausal secretory endometrium was as- sitive Swyer test yet give acceptable bleeding patterns. Any sessed for each parameter and the relative potencies calculated. new delay of menses type studies would have to be designed They found LNG to be eight times more potent than noreth- and interpreted differently than the classical Greenblatt–Swyer indrone (NE) (Table 4). methodology. Progestin potency – Assessment and relevance to choice of oral contraceptives 251

Table 4 Relative potency of commonly available progestins. Norethindrone = 1. Method of assessment Progestin Reference LNG NEA GTD DSG NG DRSP Endometrial morphology and 4.5a 4a 2.5c a – Ferin (18); b – Grant (20); c – Wiegratz et al. (13) Sub-nuclear vacuolation 1.3b 2b Endometrial biochemistry and 8d 20e d – King et al. (21); e – Byrjalsen et al. (22) Morphology including receptors and PP14 Delay of menses 60f 2f f – Greenblatt (23); g – Swyer (31) 6g 0.5g 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.

4. The role of progestin potency in the causation and prevention In both studies the definition of progestin potency was the old- of disease er Ferin and Grant glycogen vacuolation tests. The two studies produced conflicting results. The Lurie study found that the Oral contraceptives (OC) have well-established positive and strongest risk reduction for ovarian cancer was associated with negative features (9). The benefits include decreased menstrual combined oral contraceptives with low-potency progestins blood loss and decreased dysmenorhea, relief of endometriosis while the Schildkraut study found that the high-potency prog- and protection against ovarian and endometrial cancer. The estins gave the greatest risk reduction in ovarian cancer. drawbacks include increased tendency to venous thromboemo- The central problem with both these studies is that a good bolism and myocardial infarction and stroke possibly due to deal of the experience was based on patients using 30 lg EE2 lipid and carbohydrate and other metabolic changes (9). Some formulations and the potency data which they used was based attempts have been made to correlate the progestogenic effects on 50 lg EE2 formulation data. Progestin potency is highly of OCs with the potency of the progestin being used (33). dependent on the concurrent EE2 dose and it would be inter- esting to see what differences there would be if the progestin 4.1. Progestin potency and breast cancer potency calculations were adjusted accordingly (25,32,41,42).

Pike and co-workers published a case control study implying 4.4. Progestin potency and metabolic and cardiovascular effects that the risk of breast cancer was increased in users of high po- tency progestins (34). They based their potency estimates on The effects of combined oral contraceptives on lipid and car- the earlier Greenblatt data. The study was largely discredited bohydrate metabolism and in coagulation, venous thrombo- for many reasons. It did, however, result in a renewed interest embolism and arterial diseases have been well studied and in the concept of progestin potency. The role of the combined documented (9). estrogen–progestin compounds in the etiology of breast cancer There is no good evidence that progestin potency per se is remains obscure. significant in these effects. Dorflinger attempted to correlate the progestin potency with lipid changes in OC users (1). Many 4.2. Progestin potency and endometrial cancer possible factors influence lipid metabolism and the effect of progestin potency is not quantifiable. 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 5. The role of progestin potency in choice of oral contraceptive 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 Goldzieher has highlighted their problem of choosing oral con- and Grant and Ferin’s subnucleolar vacuolation tests to quan- traceptives based on potency alone (26). He also discussed the tify progestin potency in their studies (37). Maxwell et al. found problems of extrapolating animal data to humans, and the role that the potency of progestin in most oral contraceptives was of progestin metabolism as overriding factors (41,42). adequate to provide protection against endometrial cancer Historically the potency issue is an offshoot of the ‘low and that higher potency progestins may be more protective dose’ label applied to combined oral contraceptives. The limi- especially in women with a larger body habitus (35). In their tations of this label have also been previously examined (25). study Voight et al. found that the reduced risk of endometrial Enovid the original birth control pill contained 150 lg mes- cancer in oral contraceptive users was due to the progestin com- tranol and 10 mg of nonethynodrel. Concurrently with attempts ponent and that the amount and potency of progestin in most to lower the amount of hormone required for effective preg- combined oral contraceptives exceeded the threshold amount nancy suppression came the synthesis of newer progestins, a needed to produce this beneficial effect (36,38). process which is still unfolding. The use of EE2 as the estrogen of choice became standard and the dose used has been lowered 4.3. Progestin potency and ovarian cancer to 15 lg in some instances. The term low dose which makes sense as far as the estrogen is concerned became confusing for the pro- Lurie et al. (39) and Schildkraut et al. (40) examined the role gestin content of the OC because of the widely varying doses re- of progestin potency in reducing the risk of ovarian cancer. quired for efficacy. The term ‘low dose’ made no sense for 252 N. Goldstuck progestins because on a weight for weight basis some were ines the role of progestin potency in choosing progestins in clearly more active (‘potent’) than others. health and disease and the particular relevance to choice of The manufacturers of the progestins which were more ac- OCs. An attempt has been made to bring some clarity to what tive and hence required less compound on a weight basis, were is sometimes a confusing subject. quick to label their product as ‘low dose’. Those who used more progestin on a weight basis claimed their products were Appendix A. ‘less potent’ and so the controversy began. It becomes obvious that for a fixed dose of EE2, the amount and potency of the In order to exhibit progestogenic activity a steroid has to progestin being used must be taken into consideration. Gold- have a 3 keto group and a double bond between C4 and C5 in stuck has defined the term ‘effective progestin activity’ (EPA) ring A (D 4–3-keto group). which is the progestin dose multiplied by the potency (25). As would be expected when one calculates the EPA’s for the Those progestins which lack this are prodrugs and are con- various OCs there is far less variation than for the dose ranges. verted after oral administration into this form e.g. desorgestrel The EPA probably correlates more closely with OC prob- or norgestimate. These prodrugs are not active parenterally lems e.g. breakthough bleeding and other side effects of OCs and their active metabolites etongestrel or norelgestromin but this has never been examined in detail. Progestin potency must be used in the vaginal ring or hormonal patch, for itself is not, therefore, a factor in the clinical choice of the instance. OC. Choice of OCs must be made taking into account not only Pregnanes are progesterone derivatives with absence of a the dose of estrogen and progestin, but also the various clinical methyl group at C6. The 19 norprogesterone derivatives differ factors. from the progesterone derived pregnanes by the absence of a methyl radical at C-19. 6. Conclusions Estranes and gonanes are 19-nortestosterone derivatives. Estranes have no methyl group between ring A and B and have The significance of progestin potency is losing its relevance, as an ethinyl group in position 17a. Gonanes also have an ab- newer more receptor targeted progestins are becoming avail- sence of a methyl group between rings A and B and an ethinyl able. Progestin receptors are ubiquitous in the body. Proges- group in position 17a they also have an ethyl group in position tins which stimulate the receptors which lead to inhibition of 13. 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