Comparison of Substances in Combined Oral Contraceptives Used in Acne Vulgaris, Hirsutism, Migraine, and Dysmenorrhea

Introduction

Combined oral contraceptives (COC) are widely used not only for contraception, but also a therapeutic option in conditions such as acne vulgaris, hirsutism, migraine, and dysmenorrhea. Their effectiveness results from the effect of estrogen and progestogen components on androgen synthesis and ovulation, which can lead to symptom relief in these disorders. However, the benefits of COC must be weighed against the risk of adverse effects, including thromboembolic complications, particularly in women with additional risk factors [1,2]. The optimal choice of hormonal preparation and dosing regimen remains a matter of debate, especially considering the need for individualized therapy according to patient characteristics and comorbidities. This review aims to summarize current evidence on the efficacy and safety of different COC formulations in the treatment of acne vulgaris, hirsutism, migraine, and dysmenorrhea, with particular emphasis on the clinical context and the need for personalized management [3].

This narrative review assessed and compared various theoretical approaches. Studies showing the advantages and disadvantages of specific oral contraceptive substances are presented, then examples are given of patients for whom they would be the best choice.

This review aimed to answer in the following questions: Is there is an ideal combined contraceptive pill that can be prescribed to every patient? Which combined contraceptive pill is best in a particular patient? In which conditions are COCs therapeutic? What are the limitations of the substances concerned, including potential adverse effects?

A comprehensive search was performed in 3 major scientific databases: PubMed, Google Scholar, and Scopus, covering publications up to March 2025. The search strategy was based on the following predefined keywords: Oral contraceptive, Combined oral contraceptive, Acne vulgaris, Hirsutism, Migraine, and Dysmenorrhea. To enhance the completeness of the review, the reference lists of selected articles were also manually screened for additional relevant studies. The article inclusion criteria were: original research articles; systematic reviews and meta-analyses; case reports addressing rare or novel aspects of COC therapy; studies focusing on the use of COCs in the treatment of acne vulgaris, hirsutism, migraine, or dysmenorrhea; and publications available in full text and written in English. We excluded articles not published in English, conference abstracts, letters to the editor, publications without available full text, narrative reviews, studies not directly related to COC use in the specified clinical conditions, publications with insufficient methodological quality, or lacking relevant clinical outcomes for this review.

Each included study was assessed for methodological rigor (eg, randomization method, sample size, length of follow-up), clinical relevance, and compliance with the inclusion criteria. Extracted data included: characteristics of the study population (eg, age, comorbidities such as PCOS), type and dosing regimen of the oral contraceptive used, primary clinical outcomes (eg, reduction of acne lesions, frequency or intensity of migraine, severity of dysmenorrhea), and safety profile (eg, adverse effects, thromboembolic events). The strategy of studies qualification for this paper is visualized in the flowchart in Figure 1.

The results were organized thematically by condition and analyzed comparatively, focusing on treatment efficacy and tolerability. Individual factors potentially influencing treatment response (eg, BMI, ethnicity, hormonal status) were also considered. Identified limitations of the available literature (eg, small sample sizes, lack of direct comparisons, short follow-up durations) were noted and discussed.

A total of 24 articles met the inclusion criteria and were included in this review. For clarity and better visualization, the studies were categorized into 4 thematic groups based on the clinical indication addressed: acne vulgaris, hirsutism, migraine disorders, and dysmenorrhea.

Acne Vulgaris

Acne vulgaris is one of the most common inflammatory skin diseases in the world, most commonly affecting people aged 15 to 20 years. The symptoms of acne and its sequelae, such as scarring and hyperpigmentation, often lead to psychological and social problems [4]. The pathogeneses of acne vulgaris includes androgen-induced hypertrophy of the sebaceous glands, excessive sebum production, abnormal keratinisation of the follicular ducts, microbial colonization, and immune-mediated inflammatory reactions [5]. Acne in pre-pubertal girls is associated with high concentrations of dehydroepiandrosterone sulfate in the blood. Estrogen and progesterone derivatives are androgen synthesis inhibitors, so a combined oral contraceptive (COC) could be an effective therapy [2].

We found 6 articles evaluating the effectiveness of COC in treatment of acne vulgaris (Table 1) The studies included both randomized placebo-controlled trials of ethinyloestradiol (EE)/chlormadinone acetate (CMA) and EE/drospirenone (DRSP) and cohort studies (EE/dienogest). Most of them found a significant reduction in the number of inflammatory and non-inflammatory lesions in the groups taking COCs compared to placebo or other hormonal regimens. For example, in a 2009 study, 64% of women treated with EE/CMA showed a clinical response compared to 44% in the placebo group, while in a cohort study by Palacio-Cardona (2017), almost half of the patients had a 90% to 99% reduction in the number of acne lesions [2,3]. A study comparing EE+desogestrel (DSG) with EE+levonorgestrel (LNG) demonstrated the superiority of third-generation OCPs in reducing the severity of lesions. A study using EE/DRSP found a significantly greater clinical improvement and a 3-fold increase in the chances of achieving ‘clear’ or ‘almost clear’ skin [6]. In a large multicenter study involving 450 women with premenstrual syndrome symptoms, the use of EE/DRSP (20 μg/3 mg, 24/4 regimen) significantly improved scores on the Daily Record of Severity of Problems scale compared to placebo, and a clinical response (≥50% reduction in symptoms) occurred in 48% of patients in the active group vs 36% in the placebo group [7,8]. The study by Moubasher et al (2020) showed the combination of EE and LNG is more effective in reducing testosterone levels and improving the clinical picture than LNG alone [9]. In terms of methodology, most studies were of moderate quality: some were randomized, others were observational, and the observation period ranged from 6 to 12 months. Limitations included relatively small study groups in some trials and the lack of uniform criteria for assessing acne. Combined oral contraceptives, especially those containing EE with chlormadinone, dienogest or drospirenone, are effective in reducing acne lesions in women. The results also suggest that the choice of progestogen can influence the effectiveness of treatment, but the differences between individual preparations require further study.

Hirsutism

Hirsutism is the excessive growth of terminal hair in a male-pattern distribution in women, often indicating elevated androgen levels. Polycystic ovary syndrome and idiopathic hyperandrogenism account for over 85% of hirsutism cases. Less common causes include idiopathic hirsutism, non-classic congenital adrenal hyperplasia, androgen-secreting tumors, medications, hyperprolactinemia, thyroid disorders, and Cushing syndrome. Due to the high level of androgens in hirsutism, it can be treated with pharmacologic agents like COC. Therapies should be applied for at least 6 months before considering a change in treatment [10].

We found 4 articles evaluating effectiveness of COC in the treatment of hirsutism (Table 2).

A systematic review from 2020 found that COCs are less effective than combined COC+metformin therapy, although the quality of evidence was low and no significant differences were found in adolescents. In a clinical trial by Kumar et al including 90 patients with PCOS, 3 strategies were compared: metformin, COCs, and combination therapy. All groups showed improvement in clinical parameters, but the best effects in terms of reduction of inflammatory markers, insulin resistance, and body composition were observed in the combination therapy group [11,12]. Several studies have evaluated the efficacy of COCs alone. In a study by Plewig et al of 377 women, the use of EE/CMA for 6 cycles was associated with a significant reduction in hirsutism symptoms compared to placebo [2]. Sanam and Ziba (2011) demonstrated the superiority of COCs with DSG (DSG+EE) over those with levonorgestrel (LNG+EE) in reducing hirsutism [5]. However, in a small study of 20 patients by Moubasher et al, a statistically insignificant decrease in free testosterone levels was found after 6 months of LNG/EE use compared to LNG alone [8]. In terms of methodology, the studies varied from large randomized trials to small observations, often with a short observation period (eg, can reduce hirsutism, but the effectiveness varied depending on the type of progestogen used. Adding metformin to therapy can improve metabolic parameters and enhance the clinical effect, but data are limited and require further high-quality research.

Migraine

Migraine is one of the most common neurological problems in healthcare, affecting approximately 2% of the entire population. Research indicates that it predominantly affects women (18% in women vs 6% in men). Furthermore, studies have shown that women with migraines have significantly longer attack durations and greater pain intensity than men. The main classification of migraine is migraine with aura or without aura. Migraine in women is significantly associated with hormonal fluctuations, specifically those that occur naturally during the menstrual cycle. Therefore, in medical terminology, menstrual migraine is also recognized, which typically lacks an aura and affects up to 60% of women with migraines in the general population [13].

We found 3 articles evaluating the effectiveness of COCs in treatment of migraine (Table 3). A 2011 study with 60 participants compared 2 EE/DRSP regimens (21/7 vs 24/4) in women with menstrual migraine without aura. Both groups had a significant reduction in the intensity and duration of attacks, but the 24/4 regimen was clearly more effective, perhaps due to the shorter hormone-free period and reduced oestrogen decline [14]. A study by Sezgin et al (2023) involving 268 women after cryptogenic ischemic stroke and 268 women in the control group showed that the use of COCs triples the risk of cryptogenic stroke, regardless of the presence of other vascular risk factors (eg, smoking, hypertension, migraine) [15]. In contrast, a cross-sectional study by Vitali-Silva et al (2023; 486 participants) found a potential protective effect: women using COCs were less likely to experience allodynia, which is associated with chronic migraine. This effect was observed regardless of the EE dose and was particularly evident among women using oral preparations [16]. Methodologically, the studies varied significantly, ranging from small randomized trials to large cross-sectional studies, making direct comparisons difficult. COCs can have both beneficial and adverse effects on migraine patients. The 24/4 EE/DRSP regimen appears to be more effective in reducing menstrual migraine attacks, while long-term use of COCs may increase the risk of ischemic stroke. Additionally, there is evidence of reduced allodynia in women using COCs, which may indicate a role in preventing chronic migraine.

Dysmenorrhea

Primary dysmenorrhea is defined in the literature as menstrual pain without pelvic pathology. According to available sources, it affects 50% to 90% of adolescent girls and women of childbearing age [6]. Primary dysmenorrhea typically begins during the first menstruation or within 6 to 12 months thereafter, as it occurs only during ovulatory cycles. This pain is described as sharp and predictable, lasting up to 72 hours, with the most intense phase occurring on the first or second day of the cycle. The area of pain can extend beyond the lower abdomen to the lower back and thighs [17]. At the core of this issue is the excessive production of endogenous prostaglandins by the endometrium, resulting in uterine muscle ischemia due to increased contractility, and consequent pain. COCs inhibit ovulation, thereby reducing prostaglandin synthesis (PG), suggesting that they can help alleviate painful menstrual symptoms [18].

We found 4 articles evaluating effectiveness of COC in the treatment of dysmenorrhea (Table 4). A 2020 Japanese study of 186 patients showed that EE/DRSP therapy in a 24/4 regimen significantly improves quality of life in terms of pain reduction and social, mental, and physical functioning. Moreover, after therapy, quality of life was better that in the general population [19]. Strowitzki et al compared the classic regimen (28 days) with flexible, extended (24–120 days of continuous use) EE/DRSP in women with moderate to severe primary dysmenorrhea. The extended regimen was more effective in reducing the number of days with pain and the intensity of symptoms, while maintaining an acceptable safety profile [20]. A smaller study of 5 women showed that EE 50 μg therapy with lynestrenol 1 mg/day reduces uterine muscle tension as assessed by hysteroscopy and leads to a significant reduction in pain, including complete resolution of symptoms in some patients [21]. A 2023 systematic review of 21 RCTs by Schroll et al found that COCs are more effective than placebo in relieving painful menstruation, although there is no clear evidence of their superiority over non-steroidal anti-inflammatory drugs (NSAIDs). The effectiveness of treatment should be weighed against the risk of adverse effects such as irregular bleeding, headaches, and nausea [22]. COCs, especially EE/DRSP-based regimens, are effective in reducing menstrual pain and improving quality of life. Extended regimens may offer additional benefits in reducing the number of days with pain. Nevertheless, the lack of a clear advantage over NSAIDs suggests that the choice of therapy should be individualized according to patient preference, symptom severity, and safety profile.

Conclusions

Our review of the literature raises the questions of whether there is there an ideal COC that could be prescribed to all patients, and is it worthwhile to include hormonal treatment at all, when COCs are so controversial and their potential adverse effects are feared.

The differences between preparations are due to the properties of the progestogens, including anti-androgenic potency and safety profile. CMA, DNG, and DRSP have the strongest anti-androgenic effect and produce the best results [2,7]. DSG is more effective than LNG, but its anti-androgenic effect is moderate [5]. LNG is the progestogen with the lowest anti-androgenic potential of those listed – it is still effective, but is less effective in the treatment of acne than the newer substances [8]. DRSP additionally lowers free testosterone concentrations, resulting in better control of hyperandrogenic symptoms. The cited clinical studies and systematic reviews confirm the superiority of modern progestogens (CMA, DNG, DRSP) over older ones (LNG) in the treatment of acne and hirsutism in women using COCs. Studies indicate that progestogens with varying androgenic activity, such as LNG, can increase the risk of cardiovascular complications, which is particularly important in women with a predisposition to migraine or a history of thrombosis [23]. DRSP works well in patients with migraine without aura. COCs with oestrogen are contraindicated in women with migraine with aura due to the risk of vascular complications and the possibility of migraine exacerbation [13]. EE used in monotherapy results in a 3-fold increased risk of cryptogenic stroke [14]. This raises other questions: how can we monitor patients with migraine using COC to minimise the risk of complications? Does COC alter brain neurochemistry in a reversible way? Pills with DRSP are preferred for the treatment of primary dysmenorrhea due to their strong analgesic effect, good metabolic profile, and additional benefits, such as improved quality of life. Flexible and 24/4 regimens can reduce the number of days with pain more effectively than the classic 28-day regimens [18–20].

There are still many important knowledge gaps regarding the use of oral hormonal contraception to treat conditions such as acne, hirsutism, migraine, and painful menstruation. Comprehensive studies analysing how individual factors such as BMI, ethnicity, the presence of PCOS or genetic predisposition affect the efficacy and safety of therapy are lacking. It is known, for example, that women with a BMI below 20 kg/m2 respond better to acne treatment, but the mechanisms behind this phenomenon remain unclear. New generations of progestogens, such as the combination of estetrol and drospirenone, require further comparative studies of cardiovascular safety and efficacy in treating symptoms of androgenization [24].

Another gap is the lack of data on the long-term effects of continuous regimens (28/0), which could theoretically minimize estrogen withdrawal-related symptoms such as migraines or painful menstruation, but their efficacy and safety need to be determined in clinical trials. Direct comparisons of different dosing regimens (21/7, 24/4, 28/0) in terms of efficacy in the treatment of menstrual migraines, impact on thrombosis risk, and patient acceptance are also needed [13]. Additionally, a Japanese study showed that the use of EE/DRSP on a 24/4 cycle improves wellbeing and reduces pain, suggesting that this treatment regimen may be more beneficial than other available options for the treatment of dysmenorrhea [18]. There are still insufficient data on the safety of COCs in women with migraine with aura or a history of thrombosis, as well as on the interaction of COCs with antiepileptic, antidepressant, and antiretroviral drugs. There is also a lack of imaging studies (MRI/fMRI) assessing the long-term effects of COCs on brain structure and function, such as grey matter changes, neuronal connectivity patterns, or stress responses, considering the patient’s age at therapy initiation, genetics, and duration of use.

In addition, less than half of women using COCs receive information about therapeutic benefits beyond contraception (eg, in treatment of endometriosis), indicating the need to develop more effective educational strategies tailored to different ethnic and socio-economic groups. Finally, innovative hormone delivery systems, such as intrauterine systems with UPA or transdermal combination systems, require further research on efficacy, bioavailability, and stability of hormone concentrations. All these gaps point to the need for multidisciplinary research with large groups of patients, using advanced molecular and imaging techniques, to enable optimisation and personalization of hormone therapy.

The choice of an appropriate COC should always be individually tailored to a woman’s health needs, not only to prevent pregnancy, but also to treat conditions such as acne, hirsutism, menstrual migraine, and painful periods. Hormonal preparations vary in their efficacy and safety profile depending on the clinical problem and patient characteristics (eg, BMI, PCOS, risk of thrombosis). The optimal treatment can significantly improve quality of life, but requires an informed choice and consideration of individual contraindications and risk of adverse effects.

There is no single ‘perfect’ COC for everyone. The choice of hormonal contraception should be based on medical indications and patient safety. COCs can be effective in relieving the symptoms of acne, hirsutism, menstrual migraine, and painful menstruation, but require an individualized approach and monitoring.