Let’s reconsider modern progestin-only pills during isotretinoin and retinoid therapy

Retinoids are derivatives of vitamin A (retinol) and have been used in medicine as regulators of growth, differentiation, cell cycle progression, apoptosis and cell survival in a variety of cell types, especially epithelial and sebaceous cells [1]. Retinoids are usually classified in one of three generations. However, some researchers consider pyranones derivatives as the fourth generation [2]. The synthesis and development of retinoids has represented a milestone in the management of several dermatoses such as acne, psoriasis, ichthyoses, and more recently, severe chronic eczema of the hands [2]. In the early seventies, a few dermatologists investigated the efficacy and safety of oral 13-cis-retinoic acid (isotretinoin) in acne patients obtaining excellent clinical results [3–5]. Oral isotretinoin was therefore approved for treatment of severe acne by the US Food and Drug Administration (FDA) in 1982. To date, the efficacy of isotretinoin has not been superseded by any other treatment and over four decades later, isotretinoin remains the most clinically effective anti-acne therapy, producing significant improvement in many patients and long-term remission [6].

Several adverse effects have been associated with isotretinoin, but by far the most important is the teratogenicity induced by this drug [7–9]. Exposed infants in utero have 20–35% risk of numerous congenital defects, such as craniofacial, cardiovascular and neurological malformations or thymic disorders [9,10]. To avoid retinoid exposure during pregnancy, several risk minimisation measures (RMMs) have been developed, and numerous pregnancy prevention programs (PPP) were implemented by regulators worldwide, embracing issues around education, therapy management and control of drug distribution [11,12]. The first PPP associated with isotretinoin was promotoed by the manufacturer (Roche) and consisted of patient education brochures describing the risks of isotretinoin, including teratogenicity [11]. Since then, both the FDA and the European Directive have developed PPPs supporting the complete awareness of patients and prescribers of teratogenicity risk, requiring the patient to acknowledge the risk, supply informed consent, and undergo detailed counselling by the clinician prior to and during treatment [10]. Therapy management includes medically supervised pregnancy testing before, during and after therapy, including the use of at least one effective method of contraception (preferably a user independent form such as an intra-uterine device or implant) or two complementary forms of contraception, including a barrier method [12,13]. Currently, differences among national or federal regulatory agencies has resulted in worldwide non-uniform management of teratogenic risk and prescription requirements associated with retinoid therapy.

According to the last version of US iPLEDGE Risk Evaluation and Mitigation Strategy (REMS), ‘Progesterone-only “mini-pills” are unacceptable forms of contraception’ during retinoid therapy [14].

This recommendation is based on few evidences. A small study of 26 subjects conducted 20 years ago, proving the Cmax of first generation progestin norethindrone (NET), part of a combined oral contraceptive (COC) regimen with ethinyl-estradiol (EE), decreased by 11% on day 20 of a treatment cycle during concomitant isotretinoin therapy. However, the same study reported decreased levels of EE (9% decrease in area under the plasma concentration-time curve on day 6) and the authors concluded that the small reduction in EE and NET levels during isotretinoin concomitant therapy was not associated with any clinically relevant pharmacodynamic changes [15]. Another very small study including 9 subjects investigated acitretin with concomitant COCs or older generation mini-pills (containing levonorgestrel 30 µg). No contraceptive interference with COCs was documented but a possible interferenace was noted with a very low dose older generation mini-pill [16]. No other research has been conducted since then with any newer generation ‘mini-pills’ or ‘progestin-only pills’ (POP).

The distinction between ‘mini-pills’ and ‘POPs’ should be considered, as these terms do not indicate the same drug entities and should not be considered synonymous. ‘Mini-pill’ prescriptions began in the mid-1960s, following the discovery that small doses of progestins could prevent pregnancy, although not preventing ovulation. The term ‘mini-pills’ came from the fact that these pills contained only synthetic progestins in low doses, lower than in combined pills [17]. The supplementary contraceptive mechanisms of action of these pills include a partial action on the hypothalamic-pituitary function and an alteration of the cervical mucus and endometrium. Despite a large market offering over many years, the ‘mini pill’ does not represent a valid alternative to COCs, as a complete suppression of ovulation is not guaranteed, not providing an equal effectiveness to that of COCs [18]. In particular the NET mini-pill contains a dose of 35 µg of the progestin, whereas the dose requested to inhibit ovulation is 50 µg for NET. For this reason, a revolution in progestin only oral contraceptives occurred in 2002 when, in Europe, the desogestrel (DSG) 75 µg was launched. This was the first real POP containing a progestin dosage that allows the complete inhibition of ovulation [19].

In 2021, a novel POP was launched containing drospirenone (DRSP) (drospirenone-only pill, DOP) 4 mg (in a 24 + 4 regimen), an anti-androgenic progestin useful in women suffering from acne. Moreover, the DOP, compared to all other POPs, is associated with a better bleeding profile with higher rates of scheduled bleeding and lower rates of unscheduled intracyclic bleeding or spotting [20]. This formulation led to better acceptability rates and therefore, it can be considered a first choice option in a much larger population, than older generation POPs and mini-pills [21]. Both DSG and DRSP are used in new generation POPs at higher doses than those required for the inhibition of ovulation [75 vs. 60 µg for DSG (125%) and 4 vs. 2 mg for DRSP (200%)].

Isotretinoin is considererd a cytochrome P-450 3A4 (CYP-3A4) enzyme inducer that can reduce circulating progestin levels in hormonal contraceptives users, decreasing the efficacy of some progestin-only contraceptives, for example subdermal implants [22,23]. However, it remains to be demonstrated if isotretinoin can impair the contraceptive efficacy of new generation POPs by significantly reducing their circulating hormonal levels. Indirect evidence against this scenario can be found in a recent study of progestin subdermal implant which demonstrated that the contraceptive efficacy of etonogestrel (a metabolite of DSG) was not reduced during isotretinoin therapy [24].

Therefore, further investigations about the use of new generation POPs should be considered for women under isotretinoin therapy who present contraindications to combined products, even considering that clear experimental and biological evidence against their efficacy seems to be lacking.

Acknowledgments

The authors would like to thank Johanna Chester for language editing and editorial assistance.

Disclosure statement

G. Grandi received honoraria for sponsored lectures and participation in advisory boards from Bayer AG, Theramex, Exeltis, Organon, Italfarmaco, Opocrin and Gedeon Richter. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.