Progestogen-only oral contraceptives.

The bleeding pattern with the use of POPs is variable, ranging from amenorrhea to frequent and irregular bleeding. In general, women exposed to minipills such as norethisterone will continue to ovulate and have regular cycles, while those who experience ovarian suppression will have irregular and unpredictable bleeding. The mechanisms involved in bleeding during the use of progestogen-only pills are not well established. Possible explanations for the bleeding alterations when using contraceptives include more changes in tissue perfusion in combination with local angiogenic factors, together with the permeability of superficial vessels and the change of receptor functions for endometrial steroid hormones. 28 In fact, irregular bleeding is the most commonly cited reason for discontinuing POPs, and occurs in up to 25% of users. 14 29 The WHO recommends using the analysis by “reference period” (RP), 30 defined as periods of time measured in number of days to analyze the bleeding pattern with different contraceptives. In most current studies, the 90-day RP is used to characterize the bleeding pattern with hormonal contraceptives, particularly with progestogens alone. In a one year follow-up study, two progestogen-only contraceptives, desogestrel 75 mcg and levonorgestrel 30 mcg, were compared. 14 The analysis of the bleeding pattern followed the WHO nomenclature. In the RP, about 50% of women on desogestrel 75 mcg experienced amenorrhea or infrequent bleeding compared to 10% of levonorgestrel users. Only 4% of women on desogestrel experienced frequent bleeding, in contrast to 10% of women in the levonorgestrel group. The incidence of prolonged bleeding decreased with time in both treatment groups. As the regimen of drospirenone alone has a four-day break between active pills, the bleeding profile is distinct, and evaluated in 30-day RPs. In a phase 3 double-blind, randomized, controlled clinical trial study involving healthy women aged 18-45 years, the bleeding profile of the contraceptive containing drospirenone only (4 mg) on a 24/4 cyclic regimen was compared to the contraceptive containing desogestrel (75 mcg) used continuously over nine cycles. 31 Scheduled bleeding was defined as any bleeding or spotting that occurred during the hormone-free intervals (between days 25 and 28, ± one day), lasting up to eight consecutive days for women using drospirenone. For this group, unscheduled bleeding was defined as any blood loss or spotting occurring between days 2 and 23 of each cycle, corresponding to the period of intake of active pills. For the group of desogestrel users, definitions for scheduled bleeding were not considered, and all days of bleeding or spotting during the use of active pills were recorded. Women who used desogestrel experienced a percentage decrease in bleeding/spotting rates from 74% to 45.3% between cycles 2 and 9, respectively. When considering only unscheduled bleeding/spotting, the percentage for drospirenone users was significantly lower compared to desogestrel users, particularly between cycles 2-6 and 2-9. The mean number of days of unscheduled bleeding during cycles 2-9 was significantly lower for drospirenone (21.5 days) compared to desogestrel (34.7 days). There was also a trend towards fewer bleeding/spotting days over time for drospirenone users (mean 13.1 days between cycles 2-4 to 9.7 days between cycles 7-9). The desogestrel group experienced a mean reduction from 16.9 days to 10.8 days, between cycles 2-4 and 7-9, respectively. The number of bleeding/spotting days was lower in the group of women who used drospirenone at all defined treatment periods.

Progestogen-only oral contraceptives comprise pills composed of progestogens with distinct contraceptive properties, including central or peripheral effects. Norethisterone acetate 0.35 mg, desogestrel 75 mcg and drospirenone 4 mg are the progestogen pills available in Brazil. The main mechanism of contraceptive action of desogestrel and drospirenone is the inhibition of the ovulation. The main effect of norethisterone is the alteration of cervical mucus. Progestogens used alone for contraception that promote inhibition of the ovulation have greater contraceptive efficacy. The bleeding profile of progestogen-only oral contraceptives is regimen dependent. Desogestrel and norethisterone taken continuously have a variable bleeding pattern, ranging from amenorrhea to spotting or even irregular bleeding. Drospirenone alone in a 24/4 regimen has a predictable bleeding pattern in most cases. As progestogen pills have a lower risk of cardiovascular events, they are particularly indicated for women with contraindications to combined contraceptives, given the absence of estrogen in their formulations.

The association between POPs and the risk of various cardiovascular outcomes, including VTE, myocardial infarction, stroke, hypertension, and diabetes by route of administration was also studied. In a review of 19 studies 39 based on the random effects model, the pooled adjusted relative risks (RRs) for VTE, myocardial infarction and stroke for POP users versus non-users were 1.06 (95% confidence interval [CI]: 0.70-1.62), 0.98 (95%CI: 0.66-1.47) and 1.02 (95% CI: 0.72-1.44), respectively. No effect of POP use on blood pressure was found. Hence the assumption that the oral use of POPs is not associated with a higher risk of developing various cardiometabolic outcomes. On the other hand, women with past medical conditions that offer higher risk of thrombosis should also not use estrogen-containing contraceptives. Little is known about POPs in this situation. In the systematic review by Tepper et al., 40 most evidence do not suggest a higher risk of venous or arterial events with the use of POPs. Thus, hypertensive or smoker women can still benefit from using POPs to prevent pregnancy.

The class of progestogen-only oral contraceptives combine efficacy with very broad indications, including critical clinical situations, particularly when combined hormonal methods are not recommended. Although they are described together, progestogen contraceptive methods must be analyzed individually. The specific characteristics of each compound require a critical analysis focused on the clinical condition where the method is intended to be instituted. Note that the unpredictable bleeding pattern is the main element responsible for the abandonment of POPs. In this sense, desogestrel and drospirenone alone are different; drospirenone showed better cycle control in phase 3 studies, allowing greater contraceptive coverage in situations where estrogen is contraindicated. National Specialized Commission on Contraception of the Brazilian Federation of Gynecology and Obstetrics Associations (FEBRASGO) President: Rogerio Bonassi Machado Vice-President: Ilza Maria Urbano Monteiro Secretary: Jaqueline Neves Lubianca Members: Carlos Alberto Politano Cristina Aparecida Falbo Guazzelli Edson Santos Ferreira Filho Jarbas Magalhães Luis Carlos Sakamoto Maria Auxiliadora Budib Mariane Nunes de Nadai Milena Bastos Brito Sheldon Rodrigo Botogoski Tereza Maria Pereira Fontes Valeria Barbosa Pontes Zsuzsanna Ilona Katalin de Jarmy Di Bella

Progestogen-only methods have few contraindications. They are also highly indicated in clinical situations in which there is an absolute contraindication to the use of hormonal contraceptives containing estrogens (combined hormonal contraceptives). The unrestricted indications (categories 1 and 2) for progestogen-only methods, when estrogen-associated methods are generally contraindicated, are summarized in chart 1. 22 BMI: body mass index; DVT: deep vein thrombosis; PTE: pulmonary thromboembolism; STIs: sexually transmitted infections; AIDS: acquired immunodeficiency syndrome; HIV: human immunodeficiency virus Source: World Health Organization. Medical eligibility criteria for contraceptive use [Internet]. 5th ed. Geneva: WHO; 2015 [cited 2021 Oct 24]. Available from: https://www.who.int/publications/i/item/9789241549158 . 22

Approximately 100 million women worldwide currently use a combined oral contraceptive (COC) containing an estrogen-progestogen combination. 1 Combined oral contraceptives are associated with a higher risk of venous thromboembolism (VTE) and cardiovascular disease. 2 3 The World Health Organization (WHO) attests that progestogen-only oral contraceptives, also known as POPs (progestin-only pills), do not offer a higher risk for VTE, myocardial infarction, and stroke. 4 In this sense, aspects related to safety may result in a greater prescription of POPs for a greater number of women eligible for this contraceptive modality. In Brazil, an analysis of 1,113 women from the supplementary health system showed that the use of a single POP, desogestrel, was reported by 18% of users of contraceptive methods. 5 The most relevant aspects of POPs should be observed in view of the option or medical indication, since all methods containing only progestogens have different biochemical and pharmacological characteristics, in addition to the contraceptive effect itself. The first question that may generate doubt refers to the “progestogen pills” term, which is widespread in the gynecological setting. This group includes compounds previously called minipills, which contained norethisterone, lynestrenol and levonorgestrel (the last two no longer available in Brazil), in addition to desogestrel alone. Recently, drospirenone alone has been incorporated into the group of POPs. 6 The contraceptive mechanism of action is different among POPs. The main mechanism of action of minipills is the alteration of the cervical mucus and secondarily, the endometrial activity hostile to implantation. 7 On the other hand, desogestrel and drospirenone alone have gonadotropic blockade as their main mechanism of action, which offers greater contraceptive efficacy for women who are not breastfeeding. 8 9 Thus, although “progestogen pills” represent the different isolated progestogens used orally, the mechanisms of action are distinct and ultimately, reveal the main characteristic of a contraceptive: effectiveness. The aim of this document is to critically analyze the main characteristics of POPs available in Brazil, with emphasis on frequently asked questions in the practice of professionals involved with the subject.

Progestogen pills containing desogestrel or drospirenone have lower failure rates due to the antiovulatory effect and should be considered for women who require highly effective contraceptives. The use of oral desogestrel alone, as well as of norethisterone, should be continuous. Drospirenone alone should be used for 24 days actively followed by a four-day interval. All progestogen-only pills are indicated and safe for use in nursing mothers. Counseling about the irregular bleeding pattern that may occur when a progestogen pill is prescribed is essential. Prior guidance leads to greater continuity and adherence to this contraceptive modality. Progestogen pills may be indicated for obese women, smokers, hypertensive or those with risk factors for cardiovascular disease. Progestogen-only oral contraceptives are not associated with a higher risk of venous thromboembolism and may even be indicated for women with a personal history of deep venous thrombosis or pulmonary embolism. There is no restriction on the use of progestogen pills by women with a history of cardiovascular disease, including myocardial infarction or stroke. Progestogen pills are not associated with reduced bone mineral density.