Drospirenone Oral Contraceptives

Nelson Soucasaux

( September 2007 )

Nelson Drawing 1978

Some years ago a new progestin ( synthetic progesterone ) named drospirenone was synthesized and, associated with the widely-known estrogen ethinyl estradiol, is now giving rise to a new generation of oral contraceptives. So, by drospirenone oral contraceptives I mean those that associate the usual ethinyl estradiol with the new progestin drospirenone. When compared to the other ones, these new contraceptives seem to possess some slightly different metabolic effects due to drospirenone's particular properties. Even so, their contraceptive mechanisms ( the ways they prevent pregnancy ) are the same of all the other combined oral ones.

When compared to all the other existing synthetic progestins, drospirenone's progestogenic effect is considered as being closer to that of natural progesterone, besides possessing a particular anti-mineralocorticoid and anti-androgenic activity. Curiously, drospirenone was chemically obtained having the anti-mineralocorticoid spironolactone as precursor ( actually, drospirenone is considered a spironolactone analogue. About that, see Note below.)

The slight anti-mineralocorticoid activity and its consequent also slight diuretic effect is due to the fact that, to some extent, drospirenone is able to reduce the effect of aldosterone. ( Aldosterone is the main adrenal hormone responsible for controlling the retention of sodium and water in the body and, therefore, the hydric balance. ) Thus, by slightly reducing aldosterone's effect and stimulating natriuresis ( the elimination of sodium and water by the kidneys ), the new "Pills" containing drospirenone are said to be able to avoid or reduce the swelling frequently associated with most of the other oral contraceptives.

"Pills" containing drospirenone are also regarded as being potentially beneficial for women who exhibit the hydric retention and swelling typical of many cases of premenstrual syndrome ( though in clinical practice the intensity of this effect may be still somewhat uncertain and, obviously, will depend on each woman's reaction to the product ). Natural progesterone also possesses some diuretic effect.

As all the other progestins contained in the usual oral contraceptives do not possess anti-mineralocorticoid effects, the sodium and water retention sometimes induced by their estrogenic component is not counterbalanced. Conversely, "Pills" containing drospirenone, due to the anti-mineralocorticoid property of this new progestin, are said to be able to oppose this sodium and water retention sometimes related to the oral contraceptives' estrogenic component ( ethinyl estradiol ).

Drospirenone is also endowed with a considerable anti-androgenic effect, though it seems to be less than that of cyproterone ( the widely-known anti-androgenic progestin used in some oral contraceptives especially developed for women with slight hypertrichosis, hirsutism and acne ). In this way, drospirenone "Pills" can also be indicated for slight androgenic manifestations in women.

The first drospirenone oral contraceptive was released some years ago, consisting of 21 tablets, each one of them containing 0.03mg of ethinyl estradiol and 3mg of drospirenone and is to be administered as usual, with a 7-days interval between each series of 21 tablets. Nevertheless, if we look at it as a "Pill" released in the time of the low-dose ones ( regarding their estrogenic component ), it cannot be considered as such since each tablet still contains 0.03mg of ethinyl estradiol. ( Over the last 10 years, low-dose oral contraceptives are those that contain 0.02mg of ethinyl estradiol .) So, this first "Pill" containing drospirenone actually is "middle-dose."

But now finally the first low-dose drospirenone "Pill" was released, and the manufacturers report a contraceptive efficacy of 99%. Including an important change not only in the number of tablets contained in each series but also in the interval between them, this new oral contraceptive consists of 24 tablets, each one of them containing 0.02mg of ethinyl estradiol and 3mg of drospirenone and is to be taken with a 4-days interval between the series. Thus, the number of tablets in each series was increased and the interval between them was reduced. Though this new product is being announced with a special emphasis as "the 'Pill' for women with premenstrual syndrome", I think that more clinical experience and time are needed so that we can have more certainty about it ( though theoretically and pharmacologically it seems to be correct ). We always must have in mind that, even after their approval and release, all new medicines require a long period of further careful observation.

Despite all of this, an aspect of drospirenone's pharmacology deserves special attention : for antagonizing aldosterone's action, there is a potential for a slight raise in the blood levels of potassium. Though this alteration does not have any importance in normal women under normal conditions, special care is required in patients who are taking a large number of very common drugs that may raise the potassium levels ( heightened potassium levels may be dangerous for the risk of causing heart arrhythmias ).

Among these drugs are potassium-sparing diuretics, angiotensin-converting enzyme inhibitors ( ACE inhibitors ), angiotensin-II receptor antagonists and other aldosterone antagonists, including spironolactone itself ( most of these drugs are used for the treatment of hypertension and related conditions ). ( As to the aforementioned relation between spironolactone and drospirenone, see Note below. ) In this way, the use of drospirenone in women taking these medicines is not advisable or demands special care and constant control of the potassium levels ( there is even a warning from the laboratory about that ).

After saying all of this, I must emphasize that the recently released low-dose drospirenone oral contraceptive - containing 0.02mg of ethinyl estradiol and 3mg of drospirenone in series of 24 tablets to be taken with a 4-days interval between the series -, though possessing very, very interesting and important features, is still too new for any adequate and correct evaluation of its long-term effects in clinical practice. So, let us see what comes ahead.

Note: Curiously, drospirenone, which is a progestin, was chemically obtained by introducing some modifications on the anti-mineralocorticoid spironolactone molecule. Here we must remark that, as synthetic sexual steroids, all previously existing progestins are also obtained having synthetic sexual steroids as precursors. In this way, the novel progestin drospirenone is a curious exception. As to spironolactone, it is an anti-mineralocorticoid diuretic that functions by antagonizing aldosterone's effect, consequently causing natriuresis ( the excretion of sodium and water by the kidneys ). Besides, spironolactone is also endowed with an anti-androgenic property and, for that reason, has been also used for the treatment of hypertrichosis and hirsutism. Considering all of this we can see that drospirenone - as a synthetic progesterone and, obviously, a sexual hormone -, very curiously was synthesized just having an anti-mineralocorticoid as precursor. Besides having acquired its remarkable progesteronic effects, drospirenone also retained the anti-mineralocorticoid and anti-androgenic effects of its chemical precursor spironolactone.

P.S.1: Please note that this article was written in July and August 2007 - that is, only a few months after the release of the first low-dose drospirenone oral contraceptive ( though "middle-dose" drospirenone "Pills" have been available in the market for approximately 4 years ). In this way, it is too early for trying to arrive at any clinically firm conclusion regarding its effects. Nevertheless, the perspective seems to be optimistic.

P.S.2: For a better understanding of this article, see also my "Oral Hormonal Contraceptives" published on this site in 2002.

Nelson Soucasaux is a gynecologist dedicated to Clinical, Preventive and Psychosomatic Gynecology. Graduated in 1974 by Faculdade de Medicina da Universidade Federal do Rio de Janeiro, he is the author of several articles published in medical journals and of the books "Novas Perspectivas em Ginecologia" ("New Perspectives in Gynecology") and "Os Órgãos Sexuais Femininos: Forma, Função, Símbolo e Arquétipo" ("The Female Sexual Organs: Shape, Function, Symbol and Archetype"), published by Imago Editora, Rio de Janeiro, 1990, 1993.

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