Newer Progestogens
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_________________________________________________________________________________________________________________ REVIEW J Fam Plann Reprod Health Care: first published as 10.1783/147118903101197188 on 1 January 2003. Downloaded from _________________________________________________________________________________________________________________ Newer progestogens Sam Rowlands, MD, MFFP, Lead Clinician in Reproductive & Sexual Health, South East Hertfordshire Primary Care Trust, Health Centre, Hitchin, UK Correspondence: Dr S Rowlands, Health Centre, Bedford Road, Hitchin, Herts SG5 1HF, UK. Tel: +44 (0) 1462 781331. Fax: +44 (0) 1462 781321. E-mail: [email protected] (Accepted 25th October 2002) Journal of Family Planning and Reproductive Health Care 2003; 29(1): 13–16 Abstract Introduction Objective. To review the literature on the most recent It is now 50 years since the first progestogens were progestogens to be developed, to provide clinical synthesised. New progestogens are being produced in order comparisons with older progestogens and to look at the to develop novel positive attributes, enhance positive potential of products not yet marketed. attributes of existing progestogens or to reduce or eliminate Data sources. Searches of Medline and Popline together undesirable attributes. In the last decade five progestogens with requests for bibliographies from the Population have been developed; these are indicated in italic type in Council, Wyeth-Ayerst Research and Schering Health Care. Table 1. Study selection. Information from technical papers was Research into new progestogens has been driven by the used to ascertain the metabolic characteristics and receptor thought that combined oral contraceptive (COC) pills tend binding affinities of the compounds. Previous reviews were to alter lipid metabolism in an adverse direction due to a scrutinised in order to make comparisons with older preponderance of androgenic properties of the progestogen compounds. Any available trials were examined to ascertain component. Effects on lipids may increase the risk of efficacy, bleeding patterns and tolerability, more weight arterial disease, although clinical studies have not being given to comparative trials. confirmed this. Even though high-density lipoprotein Discussion. Five progestogens have been developed in the (HDL)-cholesterol is decreased and triglycerides and low- copyright. last decade. They are all devoid of androgenic activity; density lipoprotein (LDL)-cholesterol are increased by some have antiandrogenic activity. Combined oral treatment with COCs containing ‘androgenic’progestogens, contraceptive (COC) pills containing dienogest and the strong direct effect of ethinylestradiol on the arterial drospirenone are already marketed. Nomegestrol and wall is thought to protect against atheroma formation, nestorone have been extensively studied as subdermal probably by preventing oxidation of LDL.1 Also, the effect implants. of COCs on carbohydrate metabolism is mainly dependent Conclusions. Newer progestogens used in combination with on the action of ethinylestradiol, modulated only slightly by oestrogen behave very similarly to existing products. the progestogen component. Progestogen-only products using new progestogens have The majority of women settle well on the traditional potential for significantly better tolerability due to their levonorgestrel or norethisterone monophasic COCs. lack of androgenic activity. (Norgestimate is largely metabolised to levonorgestrel and so is not such a novel progestogen as first thought.) If http://jfprhc.bmj.com/ monophasic pills are thought to be causing progestogenic Key message points side effects, transferring to a triphasic formulation reduces Combined oral contraceptive pills containing newer progestogens total progestogen dose per cycle. But for those who still do have not been shown so far to have appreciable advantages over not settle, the alternative pills containing desogestrel or existing formulations. gestodene have been helpful. The strong potency of these Nestorone has the potential advantage when used during lactation latter progestogens has allowed a reduction in that it is not significantly absorbed by the suckling infant. ethinylestradiol dosage to 20 µg without loss of efficacy and Nestorone implants have the highest amenorrhoea rate of any on September 23, 2021 by guest. Protected implant so far produced. this can be useful when an individual is thought to be Nomegestrol implants do not appear to have acne as a side effect. suffering from estrogen side effects and has theoretical More than half of nomegestrol implant users have a bleeding pattern advantages in possibly reducing venous thromboembolism similar to their normal menstrual cycle. risk. Table 1 Classification of progestogens 19-Nortestosterone derivatives 17a -OH-Progesterone derivatives 19-Norprogesterone derivatives 17a -Spirolactone derivative Estranes Gonanes Pregnanes Norethisterone Levonorgestrel Medroxyprogesterone Nomegestrol Drospirenone Dienogest Desogestrel Cyproterone Nestorone Gestodene Trimegestone Norgestimate (norelgestromin) Italic type is used to indicate those progestogens developed within the last 10 years. Journal of Family Planning and Reproductive Health Care 2003: 29(1) 13 Review Rowlands J Fam Plann Reprod Health Care: first published as 10.1783/147118903101197188 on 1 January 2003. Downloaded from Levonorgestrel and etonogestrel progestogen-only newer progestogens are combined with ethinylestradiol, the subdermal implants have the disadvantages of androgenic formulation is estrogen-dominant as far as metabolic effects side effects and unpredictable bleeding patterns. are concerned. The effects of the progestogens on the Progestogens without androgenic activity used in implants endometrium and cervix outweigh those of ethinylestradiol would be a significant advance. and contribute to the high contraceptive efficacy. The newer progestogens discussed in this review are all devoid of androgenic activity; indeed some have Dienogest antiandrogenic activity. Are there particular women who Dienogest exhibits weak binding affinity for the will benefit from these formulations? The COC containing progesterone receptor and negligible affinity for the drospirenone purports to have benefits from its estrogen, glucocorticoid and mineralocorticoid receptors.4 antimineralocorticoid activity. How do implants containing Nevertheless, dienogest shows a pronounced progestogenic new progestogens compare with existing products? Is there effect on the endometrium. There is low competitive a future for vaginal rings using new progestogens? binding to the androgen receptor. After oral administration, This review concerns use for contraception only. All dienogest is five times as active as levonorgestrel and 10 the progestogens mentioned have been developed with a times as active as medroxyprogesterone acetate by the view to use in hormone replacement therapy (HRT) McPhail test. Compared to levonorgestrel, dienogest has a products also.2 considerably higher fraction of free, non-protein-bound compound in plasma. This large fraction of biologically Classification of progestogens active steroid contributes to the strong progestational effect The classification of progestogens according to of dienogest. Antigonadotrophic actions, e.g. inhibition of biochemical grouping is shown in Table 1. For clinicians follicle-stimulating hormone (FSH) and luteinising this is not helpful as very minor changes to the steroid hormone (LH), are weak. Dienogest inhibits ovulation skeleton can produce major metabolic changes, for instance primarily via peripheral actions, rather than via a central halogenation of C-6 or removal of the C-19 methyl radical action on gonadotrophin secretion. Antiandrogenic activity results in compounds with much higher progestational is approximately 30% that of cyproterone acetate.1 activity. Categorisation according to ‘generations’ will not A COC containing dienogest 2 mg with ethinylestradiol be used in this review. 30 µg has been available in Germany since 1991. Efficacy is satisfactory and cycle control good.5 In a randomised, General characteristics of newer progestogens double-blind comparison of dienogest 2 mg/ethinylestradiol Newer progestogens have high progestogen potency, with 30 µg with cyproterone acetate 2 mg/ethinylestradiol 35 µg, no androgenic activity. Some have antiandrogenic activity both formulations caused increases in SHBG of 250–300%, but not as much as cyproterone acetate has. None of them reductions in free testosterone of around 70% and reductions copyright. bind to sex hormone-binding globulin (SHBG). of androstanediol glucuronide of 50–60%. Metabolic effects Progestational activity is usually tested using the were not significantly different between the two McPhail Index in immature rabbits, and also the pregnancy formulations and beneficial effects on acne were equal.6 maintenance and the ovulation inhibition tests in rats.2 Using these in vivo tests, nestorone appears to be the most Drospirenone potent progestogen, being 10 times more potent than Drospirenone on its own produces a small negative sodium levonorgestrel and 100 times more potent than progesterone balance when compared to placebo.7 Drospirenone has itself when the molecules are administered subcutaneously.3 antimineralocorticoid activity very much like progesterone; When given orally, norethisterone, medroxyprogesterone the only other COC with similar activity, but much weaker,