Non-contraceptive uses and benefits of combined oral contraception
Correspondence: Rebecca H Allen. Email: firstname.lastname@example.org
- Dysmenorrhoea can be treated successfully with combined oral contraceptives.
- Combined oral contraceptives have been shown to reduce and regulate menstrual bleeding.
- Combined oral contraceptives can treat acne in women also desiring contraception.
- Severe premenstrual syndrome may respond to drospirenone-containing combined oral contraceptives.
- Use of combined oral contraceptives decreases the risk of endometrial and ovarian cancer.
- To explain the role of combined oral contraceptives in reducing the risk of cancer.
- To identify the uses of combined oral contraceptives in treating gynaecological problems such as dysmenorrhoea, abnormal uterine bleeding, premenstrual syndrome, acne, hirsutism and polycystic ovary syndrome.
- Compared with preventing pregnancy, the risk/benefit profile of combined oral contraceptives for non-contraceptive indications may be different and women should be counseled according to their individual circumstance.
Fifty years have passed since the introduction of the first combined oral contraceptive (COC) in the USA and the UK. COCs consist of an estrogen in combination with a progestogen and work primarily by inhibiting ovulation. Since their introduction, manufacturers have reduced the dose of estrogen and progestogen in the pill, created new progestogens and estrogens, and changed dosing regimens. In the UK, approximately 27% of women aged 16–49 years report using COCs for contraception. Research has shown that, besides providing reliable contraception, COCs offer a variety of non-contraceptive health benefits and therapeutic effects (Box 1). Many women, however, are unaware of the non-contraceptive health effects of COCs. While the primary indication for COC use for most women is prevention of pregnancy, women should be counselled regarding these non-contraceptive benefits when contraception is discussed and prescribed. It is important to note that using COCs specifically for non-contraceptive indications is outside the product licence and appropriate discussions with the patient regarding this fact should be documented. Nevertheless, from the treatment of gynaecological problems to reducing the risk of cancer, COCs play an important role in any clinician's armamentarium.
Box 1. Potential benefits of combined hormonal contraception (in order of strength of evidence)
- 50% reduction in risk of ovarian and endometrial cancer.
- Improvement in acne.
- Reduction in heavy menstrual bleeding.
- Regulation of menstrual cycles.
- Alleviation of dysmenorrhea.
- Treatment of hirsutism and polycystic ovary syndrome.
- Treatment of premenstrual syndrome.
- Reduction in risk of colorectal cancer.
Dysmenorrhoea, or painful menstruation, is extremely common and can lead to absenteeism from work or school. Primary dysmenorrhoea, painful menses in the absence of pelvic disease, is caused by excess prostaglandin release leading to increased uterine contractions. COCs treat dysmenorrhoea by inhibiting ovulation and reducing prostaglandin concentrations. A 2009 Cochrane review reported that both low (≤35 micrograms) and medium (>35 micrograms) dose estrogen–progestogen pills may be better than placebo at improving pain with menstruation (pooled odds ratio [OR] for pain relief 2.01, 95% confidence interval [CI] 1.32–3.08). Many of the included studies, however, were of poor methodological quality. Nonetheless, observational studies have also reported a reduction in dysmenorrhoea among COC users.[8-10] There is no strong evidence that one pill is superior to another for dysmenorrhoea, therefore, any formulation is likely to be effective. There are also secondary causes of dysmenorrhoea, such as endometriosis, adenomyosis, or uterine fibroids, which may also respond to COCs taken cyclically or continuously.[11, 12] One study switched 50 women suffering from endometriosis from a cyclic to continuous COC regimen with 2 years of follow-up. During this period, menstrual pain scores on a 100 mm visual analogue scale were reduced from 75 to 31 on average.
Abnormal uterine bleeding
Heavy menstrual bleeding, or ovulatory menorrhagia, is classically defined as >80 ml of blood loss with each period. Heavy menstrual bleeding may also be anovulatory in nature, usually producing menometrorrhagia. A large percentage of women seek advice from their physician regarding excessive menstruation and it has a major impact on a woman's quality of life. Physiologically it makes sense that COCs should effectively reduce menstrual bleeding by inducing endometrial atrophy and regulating cycles. COCs are extensively used in clinical practice for this purpose and were shown in a small study to reduce menstrual bleeding by 43%. However, current evidence supporting the effectiveness of COCs is limited and a 2009 systematic review found insufficient evidence to support its effectiveness in treating ovulatory or anovulatory heavy menstrual bleeding. Nonetheless, a 2009 randomised controlled trial evaluated a COC containing estradiol valerate and dienogest for the indication of heavy menstrual bleeding in 136 women without recognisable pelvic pathology. The group randomised to the COC experienced a greater decrease in mean menstrual blood loss than the placebo arm, with improvements in haemoglobin and ferritin concentrations. Furthermore, observational studies have indicated that COCs can reduce menstrual blood loss and increase haemoglobin concentrations, and their use is supported in clinical practice guidelines.[15, 19] A small prospective study demonstrated that women who were started on a low-dose COC had a mean blood loss that decreased from 60.2 ml to 33.7 ml after 6 months. Depending on the size and location of uterine fibroids, COCs may also be useful for decreasing heavy menstrual bleeding associated with fibroids. Reassuringly, COCs do not seem to affect the development of fibroids.
Extending the number of active pills in COCs can decrease the amount of blood loss as well. In a trial where 90 women were randomised to either a 28-day cycle with 21 active pills or a 49-day cycle with 42 active pills, the women who took 42 active pills had fewer days of bleeding and used fewer menstrual products than the women who took the traditional 28-day cycle. The number of spotting days, however, was similar for both groups. Similarly, for women with menorrhagia due to anticoagulation or bleeding disorders, COCs may be an option to reduce menstrual flow. The ovulation suppression the pill provides will also prevent haemorrhage from a corpus luteum in these women.
In addition to treating chronic heavy menstrual bleeding, monophasic COCs can also be used to treat an acute episode of heavy bleeding by using them in high doses, taking three pills per day for 1 week, followed by daily administration for 3 weeks. After a withdrawal bleed, the woman can continue on COCs if desired for continued menstrual regulation.
COCs are also a treatment option for women who have anovulatory menstrual cycles causing metrorrhagia, menometrorrhagia, oligomenorrhoea and polymenorrhoea. COCs deliver estrogen and progestogen in such a way that menstrual regularity is restored and the development of endometrial hyperplasia and cancer is prevented. A randomised trial of 201 women using a triphasic COC compared with placebo demonstrated that 80% of 97 subjects receiving the medication had improvement in their abnormal bleeding pattern as assessed by investigators and the study participants themselves.
The regulation of anovulatory bleeding may be especially beneficial for perimenopausal women. Perimenopausal women often have irregular menstrual cycles and symptomatic hot flushes in the years leading up to complete cessation of menses. Both these symptoms can be successfully treated with COCs in healthy, non-smoking and non-obese perimenopausal women.[25, 26] In addition, perimenopausal women are at risk of pregnancy as ovulation can still occur until menopause. Because the doses of estrogen and progestogen used for hormone replacement therapy in postmenopausal women are inadequate to prevent ovulation, for appropriate perimenopausal candidates, COCs are an ideal method to provide contraception, cycle control and relief of hot flushes. It is recommended that, if desired, COCs can be used until age 50.
Acne vulgaris is a common skin condition that involves the sebaceous follicles. Increased sebum production, controlled by androgens, is one important factor in the development of acne. COCs improve acne by decreasing serum-free testosterone concentrations. This is accomplished by inhibiting luteinising hormone stimulation of ovarian androgens and increasing sex hormone binding globulin production in the liver. COCs also inhibit 5-alpha-reductase activity, which is required to convert testosterone to dihydrotestosterone in hair follicles and skin. COCs are a reasonable treatment for acne in women who also desire contraception. A systematic review of 25 randomised controlled trials concluded that COCs reduced acne severity and lesion counts compared with placebo. This review was unable to show that one type of COC was clearly superior to another in the treatment of acne. Therefore, any COC is likely to be effective in the treatment of acne.
COC treatment for hirsutism has not been as well studied as for acne. Nevertheless, physiologically it makes sense that COCs should also improve hirsutism and COCs are used clinically for that purpose. While COCs can prevent an increase in hirsutism, any existing hair will need to be treated cosmetically. Two small trials have shown that drospirenone, levonorgestrel and desogestrel-containing COCs are effective in improving hirsutism.[31, 32]
Polycystic ovary syndrome (PCOS) is a common cause of acne and hirsutism in women. PCOS is defined by the presence of at least two out of three criteria: polycystic ovaries on ultrasound, oligo-ovulation or anovulation, clinical and/or biochemical signs of hyperandrogenism. Because of the reasons outlined above, plus the treatment of oligomenorrhoea and preventing endometrial hyperplasia and cancer, COCs are considered reasonable therapy in most symptomatic women with PCOS who do not desire pregnancy. A systematic review comparing COCs with metformin for PCOS concluded, based on limited evidence, that COCs are superior to metformin in cycle control and reducing serum androgen concentrations. However, metformin may be better at reducing fasting insulin levels. The authors concluded that either therapy may be appropriate depending on the individual circumstances of the woman, and that the long-term effects for either treatment are unknown.
Premenstrual symptoms are extremely common, with up to 75% of women reporting breast tenderness, bloating, fatigue, headaches, mood swings or irritability before menses. By definition, premenstrual symptoms occur before menstruation and resolve by the end of menstruation. Premenstrual syndrome (PMS) is less common, occurring in 10–15% of women, and is usually defined as premenstrual symptoms severe enough to cause impairment of daily activity. The diagnosis is best achieved with prospective recording of symptom logs for at least two cycles and other diagnoses must be ruled out. A severe form of PMS, premenstrual dysphoric disorder (PMDD), occurs in 3–8% of women and is included in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). A diagnosis of PMDD requires prospective recording and the presence of at least five emotional or physical symptoms, one being a mood problem, as well as impairment in an activity of daily living.
The use of COCs for the treatment of PMS and PMDD is based on the premise that suppressing ovulation will reduce premenstrual symptoms. Because some women experience side effects such as bloating or breast tenderness with COCs, past studies have not always shown a benefit for PMS. Drospirenone, a new progestogen derived from spironolactone, has been studied specifically for PMS and PMDD. A systematic review evaluating drospirenone-containing COCs for PMDD concluded that there was evidence of a treatment effect, although loss to follow-up was high and only 3 months of treatment was studied. Investigators have also studied the benefit of decreasing the hormone-free interval in COC regimens for the treatment of premenstrual symptoms. Women on COCs often experience symptoms of headaches, breast tenderness and bloating during the traditional 7-day hormone-free interval. One study has also shown that an extended regimen of a drospirenone-containing COC was superior to a cyclic 21/7 regimen in decreasing premenstrual symptoms. A systematic review also showed decreased menstrual pain, headaches and bloating in extended COC use compared with cyclical use. It is likely that COCs are better at improving the physical symptoms of PMS and PMDD compared with the emotional symptoms. If emotional symptoms are predominant, then selective serotonin reuptake inhibitors are the initial treatment of choice for severe PMS and PMDD.
Cancer risk reduction
COCs offer protection against endometrial, ovarian and perhaps colorectal cancer. COC users have a 50% lower risk of developing endometrial cancer than non-users.[44-47] One large case-control study showed that as little as 12 months of use conferred protection. The longer a woman uses the pill, the lower her risk of developing endometrial cancer. A meta-analysis demonstrated that 4 years of use decreased risk by 56%, 8 years decreased risk by 67% and 12 years decreased risk by as much as 72%. The protective effect lasts up to 15–20 years after discontinuing COCs.[44, 47] COCs reduce three major histologic types of endometrial cancer: adenocarcinoma, adenosquamous carcinoma and adenoacanthoma. There is conflicting evidence as to whether variations in formulations provide different degrees of protection. Some studies showed that COCs with higher doses of progestogens provided greater protection whereas others did not.[47, 48]
Just as there is strong epidemiological evidence that COCs reduce the risk of endometrial cancer, there is also strong evidence for a reduction in ovarian cancer. The mechanism of this effect is the suppression of ovulation. A 2008 collaborative meta-analysis reviewed 45 studies that compared users of COCs to never-users. The relative risk for developing ovarian cancer for users was 0.73 compared with never-users. The relative risk was decreased by 20% for each 5 years of use and the protective effect was still present 30 years after stopping. Other studies have confirmed a risk reduction of up to 40–50%.[50, 51] Low-dose COCs (<35 micrograms estrogen) appear to confer a protective effect as well.[51, 52] There is also a growing body of evidence that women with BRCA1 and BRCA2 mutations benefit from the chemoprophylactic effect of COCs.[53, 54] There is concern, however, that oral contraceptive pills may be associated with an increased risk of breast cancer in women with mutations. While it is reasonable for women with BRCA1 or BRCA2 mutations to use COCs, the risks and benefits should be weighed up by each woman and her physician.[56, 57]
While the decreased risks of developing endometrial and ovarian cancer are well known, a lesser-known benefit of COCs is possible protection against colon cancer. In one cohort study, women who used COCs for 96 months or longer had a 40% lower risk of developing colorectal cancer compared with women who never used COCs. A large meta-analysis that included six cohort studies and 14 case control studies found an 18% reduction in colorectal cancer among COC users compared with never-users. Women who had used COCs recently experienced the greatest reduction. The Royal College of General Practitioner's Oral Contraception Study found a trend towards decreased rates of colon cancer in women who had used COCs. Compared with women who had never used COCs, current users had a 0.38 relative risk (95% CI 0.11-1.32) and ever-users had a 0.84 relative risk (95% CI 0.56-1.24) of developing colorectal cancer. The results from this cohort study, however, were not statistically significant. It is also unclear whether the dose of COCs plays a role in colorectal cancer prevention.
There are probably more data about the risks and benefits of COCs than any other medication. For most women, the health benefits of COCs outweigh the risks. Indeed, a 2010 analysis of the Royal College of General Practitioners’ Oral Contraception Study showed that women who had used COCs did not experience any increased mortality compared with non-users. COCs are also therapeutic for many disorders including dysmenorrhoea, menorrhagia, acne, hirsutism, PCOS and PMS/PMDD. While this article has addressed COCs only, it is likely that the combined contraceptive patch and vaginal ring offer similar effects. There is less evidence available, however, for the non-contraceptive effects of the patch and vaginal ring. In conclusion, appropriate candidates for COCs will benefit from both the prevention of unplanned pregnancy and the treatment of menstrual pain, heavy menstrual bleeding and acne if needed. Users of COCs will also experience a reduced risk of endometrial and ovarian cancer.
Disclosure of interests
The authors report no affiliation or financial arrangement with any of the companies or products mentioned in this article or with their competitors.