Health benefits of combined oral contraceptives – a narrative review

Abstract Purpose This review presents an update of the non-contraceptive health benefits of the combined oral contraceptive pill. Methods We conducted a literature search for (review) articles that discussed the health benefits of combined oral contraceptives (COCs), in the period from 1980 to 2023. Results We identified 21 subjective and/or objective health benefits of COCs related to (i) the reproductive tract, (ii) non-gynaecological benign disorders and (iii) malignancies. Reproductive tract benefits are related to menstrual bleeding(including anaemia and toxic shock syndrome), dysmenorrhoea, migraine, premenstrual syndrome (PMS), ovarian cysts, Polycystic Ovary Syndrome (PCOS), androgen related symptoms, ectopic pregnancy, hypoestrogenism, endometriosis and adenomyosis, uterine fibroids and pelvic inflammatory disease (PID). Non-gynaecological benefits are related to benign breast disease, osteoporosis, rheumatoid arthritis, multiple sclerosis, asthma and porphyria. Health benefits of COCs related to cancer are lower risks of endometrial cancer, ovarian cancer and colorectal cancer. Conclusions The use of combined oral contraceptives is accompanied with a range of health benefits, to be balanced against its side-effects and risks. Several health benefits of COCs are a reason for non-contraceptive COC prescription.


Introduction
the introduction of the combined oral contraceptive pill (cOcP) method of female contraception was a breakthrough, medically as well as socially.the USA Food and Drug Administration approved the first cOc in 1960 and within 2 years of its initial distribution, 1.2 million American women were using the birth control pill, or 'the Pill' , as it is popularly known.Drs Gregory Pincus and Min chueh chang of the worcester Foundation for experimental Biology and John Rock, a prominent catholic gynaecologist, were the inventors of the cOcP and were instrumental in the clinical development and testing of the birth control pill.when these scientists and clinicians may be acknowledged as the parents of the pill, the grandfather and pioneer in hormonal contraception is the Austrian physiologist ludwig Haberlandt (1885−1932), He pursued his concept of temporary hormonal contraception in the female body since 1919 and demonstrated in 1921 this concept in a female animal by transplanting ovaries from a second, pregnant, animal.
From 1923, after further successful scientific work in this field, he began highlighting the importance of clinical trials in presentations and met a lot of resistance.Against all opposition, in 1930 he began clinical trials after successful production of a hormonal preparation, infecundin, by the Gedeon Richter company in Budapest, Hungary [1,2].the first approved cOc (enovid®) contained 75 µg of mestranol and 5 mg of norethynodrel.At high doses in the past, significant adverse effects were seen, especially an increased risk of venous thromboembolism (vte).However, the modern pill preferably contains 20-30 µg ethinylestradiol (ee), and progesterone has been replaced by low doses of different synthetic progestins.with these much lower hormone dosages the risk of vte has been reduced to approximately 2-4 times the low baseline risk of vte in non-users of cOcP [3][4][5][6].Replacing ee by a natural oestrogen [1.5-2.0 mg oestradiol (e2) or e2-valerate, or 15 mg estetrol (e4)], may further reduce the vte risk [7][8][9].Other less serious side effects of the cOcP are vaginal spotting and breakthrough bleeding, especially during initial cycles, scant or missed menses, abdominal cramping, nausea, breast tenderness and breast pain, weight gain, decreased libido, mood changes and headache as summarised in recent reviews of cOcP side effects [10,11].
in general the cOcP contains an oestrogen and a progestogen for 21-26 days or longer periods (extended use), followed by a 'Pill Pause' of 2-7 days.the cOcP mimics the natural cycle but differs by using a combination of an oestrogen and a progestin in every tablet, whereas in the natural cycle there is first a 10-14-day period with the oestrogen e2 only and after ovulation for 10-14 days a combination of e2 and progesterone (Figure 1). the cOcP inhibits ovulation, which is its major contraceptive mode of action.the progestin and the oestrogen in the cOcP are together responsible for the inhibition of ovulation and for regulation of the bleeding pattern of the cOcP and prevention of endometrial hyperplasia.in addition, the oestrogen in the cOcP substitutes the loss of endogenous e2 and prevents oestrogen deficiency.An important difference between the natural cycle and the cOcP cycle is the loss of testosterone, present at higher concentrations than e2 during the natural cycle (Figure 1).this loss of testosterone is not compensated by the cOcP, and may be responsible for several unfavourable effects of cOcPs on sexual function (desire and arousal) and on mood including the occurrence of depression [14,15].the negative effects of cOcPs generally draw a lot of attention, but the multiple positive effects, summarised in this review, are underestimated and underreported.

Methods
in this paper, we critically review the present status of the data related to the 21 health benefits of cOcs we have identified.Apart from analysing previous reviews, we searched PubMed as well as the cochrane Database and Google Scholar for the various combinations of benefit and cOc.Special emphasis was paid to findings published after the most recent cOc benefit review from 2015 [Human Reprod Update].First, we searched for publications in PubMed as well as the cochrane Database and Google Scholar using the search string 'review, and (health) benefit, and oral contraception' .Second, we analysed the findings and the references in the published reviews on the benefits of cOcPs found.third, since the most recent review was published in 2015 [27], we repeated the search in the various databases for the combined following terms 'year ≥2015' , '(health) benefit' and 'oral contraception' .An overview of all reviewed references (n = 248) is presented in the Supplement.we have not included combined vaginal or transdermal contraception in our review and we also do not review the non-contraceptive health benefits of progestin-only hormonal contraception (P-only), since the adverse effects and benefits of P-only show a rather different pattern of advantages and disadvantages compared to the cOcP [29] and deserve a separate analysis.
women [30] and have an large impact on the quality of life [31].Use of the cOcP reduces endometrial proliferation, maintaining a thin and stable endometrium, which results in a decrease in blood loss during menses.the cyclic treatment regimen of cOcP, prompts a withdrawal bleeding during the hormone free period, inducing a regular bleeding profile.the health benefit of the cOcP to treat menstrual bleeding disorders has been well recognised and the cOcP is frequently prescribed to manage bleeding disorders, also by extended treatment regimen with less withdrawal bleeds.A cochrane review from 2019 indicates that use of a cOcP results in a significant reduction in HMB symptoms in 12 to 77% of women [32].the reduction of excessive menstrual blood loss also lowers the risk of menstrual related iron deficiency anaemia (iDA). in the US, approximately 4% of women suffer from iDA [33], but the prevalence is much higher in low and middle income countries (lMic), largely due to dietary iron deficiency.A demographic healthy survey in over 200,000 women in lMic, comparing cOcP users versus non-users showed that the risk of anaemia is significantly decreased by 50% after two years of cOcP use [34].Smaller studies showed that the use of the cOcP was associated with higher ferritin concentrations [35] and with a marked increase in transferrin serum transferrin and soluble transferrin receptor/ferritin ratio [36].the reduced blood loss in cOcP users suffering from HMB may lead to a the lower risk of toxic shock syndrome (tSS), a potentially life-threatening condition [37].it should be noted that after abolishment of high-absorbency tampons [38], tSS became a rare event.

Less dysmenorrhoea
Menstrual cramps and pain (dysmenorrhoea) due to uterine contractions was the first indication for cOc use and is one of the most common gynaecological disorders with a reported prevalence varying between 16.8 and 81% [39].the majority of young women experience dysmenorrhoea starting shortly after menarche.the use of cOcs is associated with a decrease in prostaglandins release during menstruation [40], which may result in a less painful menstruation.the effect of the cOcP on dysmenorrhoea has been questioned in several systematic reviews [40,41], mainly because placebo-controlled cOc studies are almost impossible and therefore lacking.However epidemiological and controlled trials and clinical experience have demonstrated the beneficial effect of the cOcP on the severity of dysmenorrhoea [42][43][44][45].More recent studies showed that these effects on dysmenorrhoea are more pronounced with extended or continuous dosing [46,47]. in women with endometriosis, cOcs have been associated with a relief of dysmenorrhoea, pelvic pain and improved quality of life [48].Schindler 2013 [25] nappi 2014 [26] B'mondes 2015 [27] hCB 2024 health benefits of CoCs related to the reproductive tract including menstrual bleeding related anaemia and toxic shock syndrome.

Favourable effect on migraine
Migraine is frequently linked to the menstrual cycle and menstrual migraine affects up to 8% of women; 6% without aura and 1% with aura [49].variations in hormone levels, high mid-cycle oestrogen levels and drops in oestrogen levels at the end of the cycle are all linked with menstrual related migraine [50,51].the use of the cOcP reduces these hormonal fluctuations and thereby the incidence and intensity of migraine.A systematic review on menstrual migraine found that treatment with triptans provides the strongest evidence for both treatment and prevention of menstrual migraine [52] and the three studies with the cOcP included in this review demonstrated a reduction in the number of migraine attacks.A prospective study in 2020 on migraine in cOcP users showed that migraine attacks were typically reported during the hormone free period [53], providing an attractive rationale for taking cOcPs continuously.Of concern is the association between migraine with aura and the risk of ischaemic stroke, which contraindicates the use of the cOcs in women with this type of migraine [54].

Less premenstrual syndrome
Premenstrual syndrome (PMS) consists of a variety of physical, psychological, and behavioural symptoms occurring during the luteal phase of the menstrual cycle and resolving during menses.PMS is very common and occurs in most women of reproductive age [55].Due the psychological and behavioural nature of most symptoms, PMS was mainly treated with psychoactive drugs, such as selective serotonin reuptake inhibitors.evidence that fluctuating levels of progesterone are involved in the aetiology of PMS have initiated research to investigate the use of the cOcP for the management of premenstrual dysphoric disorder [56,57].Placebo controlled trials have showed a positive effect on PMS by various cOc combinations [58], and by ee/drospirenone (DRSP) in particular [59,60].

Less ovarian cysts
During the menstrual cycle functional ovarian cysts may be formed if a follicle fails to rupture. the actual prevalence of ovarian cysts ranges between 2.5 and 46.7% [61].the cysts usually resolve spontaneously but can cause pain and may rarely require surgical removal.Use of cOcs reduces ovarian activity and therefore the formation of ovarian cysts.early reports of this beneficial effect originate from the 1970s with high dose contraceptives [62].A study from 1992 with different type of oral contraceptives demonstrated that reduction of ovarian cysts was still present with lower dosed cOcPs (<35 µg ee) but the effect is less compared to the higher dosed ee Pills (48% vs 76% reduction) [63].A cochrane review from 2011, including eight randomised trials with 686 women concludes that the cOcP does not cause ovarian cyst resolution and should not be prescribed for this purpose [64].

Favourable effect on Polycystic Ovary Syndrome
Polycystic Ovary Syndrome (PcOS) is a common disorder, characterised according to the Rotterdam criteria by 2 of 3 of the following symptoms: oligomenorrhea or amenorrhoea, clinical or biochemical signs of hyperandrogenism and polycystic ovaries [65].the prevalence of PcOS is estimated at between 6 and 22% [66,67].cOc use reduces ovarian androgen activity and inhibits follicular development and thereby reduces the symptoms of PcOS.A systematic review and meta-analysis confirms that the cOcP suppresses hyperandrogenism and regulates menses in women with PcOS [68].cOcs are considered the first choice treatment for menstrual irregularity in women with PcOS, including it's endocrine symptoms such hirsutism and acne (see item 7) [69].

Less androgen related symptoms
in women androgens play a key role in the reproductive system as well in other body functions including the heart, bone, muscle and brain [70].An overproduction of androgens may lead to signs of androgenization such as seborrhoea, acne, hirsutism, and alopecia.Use of the cOcP decreases androgen production, lowers the fraction of free androgens due to stimulation of sex hormone-binding globulin (SHBG) and reduces conversion of testosterone to dihydrotestosterone, the active androgen in skin and hair follicles.Acne is reported by 54% of women and is associated with increased levels of circulation androgens.Acne is sensitive to hormonal changes during the menstrual cycle [71].A cochrane review including large placebo controlled studies confirmed that the cOcP significantly reduces acne symptoms [72], and other signs of androgenization.A subtle effect of androgens in women is the effect on the voice.For female singers it has been shown that cOcs stabilise voice performance that may otherwise fluctuate during the menstrual cycle [73,74].

Lower incidence of ectopic pregnancy
ectopic pregnancy, i.e., implantation of an embryo outside the cavum uteri, has a prevalence of 1-2%.consistent with its ovulation inhibiting effect, cOc use reduces the ectopic pregnancy risk. in a study including over 1.6 million women using different types of the hormonal contraceptives, the ectopic pregnancy risk during cOcP use was less than 0.5%, and the reduction of ectopic pregnancy of cOc was significant vs. low content lNG-iUD [75].

Treatment of hypoestrogenism
in the perimenopause, e2 levels decline leading to a variety of complaints such as vasomotor symptoms and hot flushes, sleep disturbances, mood swings, menstrual bleeding disorders, vaginal dryness and bone loss.Although the risk of pregnancy is reduced in the perimenopause, contraception is still recommended for women at risk of unwanted pregnancy.HRt does not provide contraception and therefore cOcs may provide a better alternative to substitute the declining e2 levels and ameliorate the perimenopausal symptoms.Several placebo-controlled studies have demonstrated the effectiveness of the cOcP in reducing the vasomotor symptoms and improving the bleeding pattern and quality of life in perimenopausal women [76][77][78].the cOcP is regarded as an effective and safe treatment option for healthy, non-smoking perimenopausal women, taking into account the contraindications, especially the increased risk of vte in women over 40 years of age when using oestrogens [79][80][81].
the hypoestrogenic state and amenorrhoea related to anorexia nervosa and exercise-induced reproductive dysfunction is characterised endocrinologically by hypothalamic suppression of gonadotropin releasing hormone (GnRH) and pituitary gonadotrophins.cOcPs are a treatment option for this type of hypoestrogenism [23,82,83].

Less symptoms due to endometriosis and adenomyosis
endometriosis and adenomyosis are conditions where the endometrium grows outside the uterus (endometriosis) or in the wall of the uterus (adenomyosis) and are associated with pelvic pain, dyspareunia and infertility.incidences are about 10% for endometriosis [84] and 20 to 35% for adenomyosis [85].cOc use inhibits the proliferation of endometrial tissue and is used as first-line treatment for pain associated with endometriosis [86].A cochrane analysis including three randomised controlled trials, comparing the cOcP to placebo treatment in women diagnosed with endometriosis, has demonstrated an effect on self-reported pain [87]. in a review including 28 studies, comparing the cOcP with placebo or other hormone treatments the cOcP reduced endometriosis related pain significantly [48].Also, cOcs may reduce heavy menstrual bleeding and provide pain relief in women with adenomyosis [88,89].

Less symptoms due to uterine fibroids
Myoma or uterine fibroids are benign tumours of the myometrium.the incidence of fibroids is estimated to be over 60% and is higher in black than in white women [90]. in most women fibroids are asymptomatic, but in approximately 30% of those women symptoms may occur including as most prominent symptom heavy menstrual bleeding and also pelvic pain, back pain, urinary symptoms, and infertility.the use of cOc may decrease menstrual bleeding due to fibroids, but cOcPs have not been shown to have an effect on fibroid size, neither positive nor negative [91].

Less pelvic inflammatory disease
Pelvic inflammatory disease (PiD) is an infection of the upper female genital tract and occurs most often in sexually active young women.if not treated adequately, PiD can lead to infertility.A placebo-controlled case-control study in women hospitalised for the treatment of PiD demonstrated a protective effect of cOc use, especially in women using oral contraceptives for more than 12 months [92,93].this effect is thought to be related to the thicker cervical mucus due to cOcP use, creating a barrier for microorganisms.

Less benign breast disease
the relationship between cOc use and Bc has been examined in many studies, but fewer studies are dealing with the relationship between benign breast disease and cOc use [94].Benign breast disease includes fibroadenoma (FA) of the breast, chronic cystic breast disease (ccD) and breast lumps (Bl) [94]. in a hospital-based case-control study, cOc use before the first full-term pregnancy appeared to decrease the risk of benign breast disease by 40% with 1-4 years use, by 60% with 4-8 years use and by 70% when use lasted 8 years or more [95].cOc use after the first full-term pregnancy had no significant effect on this risk.cOcs reduce the risk of hospitalisation for FA and ccD, but not for Bl [94]. the lowest risk of ccD is seen in current cOcP users or in women who have used the cOcP recently and the association was stronger when use was for a prolonged period of time and for at least 2 years.the decreased risk of ccD did not persist among past cOc users who had discontinued use for more than 1 year.the risk reduction is larger with higher doses of progestins in the cOcP [94,96].

Higher bone mass and less osteoporosis
Bone growth, modelling and remodelling are modulated by oestrogens, androgens, growth hormone and iGF-1 [97].Bone mineral density (BMD) in women peaks between 20 and 25 years of age, remains constant for about 10 years, and then progressively decreases in the perimenopausal years [20].Hypoestrogenic states increase the rate of bone loss [19].cOcs provide oestrogen replacement and are beneficial for BMD and reduce osteoporosis.cOcs containing <30 µg ee may be less effective in preserving bone than ≥30 µg ee pills, but no confirmation could be found in the literature [98,99].Prospective studies have found that perimenopausal women using cOcs maintain BMD when compared to women without cOc use. the longer the duration of cOcP use, the greater the protective bone effect [100,101].the use of cOcs in the past is related to higher bone mass in women reaching menopause [102]. in a large case-control study from Sweden ever-use of cOc was found to reduce hip fracture risk with 25% compared to non-users (OR 0.75; 95%ci 0.59-0.96)[103]. in a systematic review of 32 studies a positive effect of cOcs on BMD was observed in 19 studies, whereas in 13 studies no effect was found, while no studies showed a negative effect on BMD [104]. in a systematic review, in premenopausal women, cOcs have been shown to improve skeletal health (BMD and fracture rate) or showed no effect [105].

Potentially favourable effect on rheumatoid arthritis
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and symptoms include fatigue, malaise, morning stiffness, localised pain, weakness and swelling of several joints [106].Females are more often affected than males.Most commonly RA is diagnosed between 30 and 50 years of age [106].cOc use has not been investigated extensively in patients with RA.Patients with an autoimmune disorder such as RA are often prescribed contraception because of the teratogenic potential of the disease-modifying antirheumatic drugs used [107].A prospective study of females with RA diagnosed according to the American college of Rheumatology criteria found that women who used cOcs for at least 12 years, had less radiological joint damage and disability with a trend to a protective effect in patients with more severe forms of RA [108]. in a meta-analysis, evidence was found for a protective effect of cOcs on the development of RA [109].long-term cOc use before the diagnosis of RA is made shows a longer period of time without disease compared to women who never used cOcs [108]. in a Swedish study, patients who had ever used cOcs had a 19% lower chance of developing RA compared to those who never took cOcs, especially when taken for a longer period of time [110].theoretically, the oestrogen in cOcs may have an anti-inflammatory activity and thereby reduce disease activity and severity [111][112][113].this hypothesis was supported by other studies in which the use of cOcs in the past tends to have an inverse relationship with the development and progression of RA, especially in women between the age of 16 to 40 years [114,115].cOcs most likely prevent progression of RA in females as shown by having less radiological joint damage, immobility and disability with long-term use of cOcs [107,109,116].

Potentially favourable effect on multiple sclerosis
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system including inflammation, myelin damage and progressive neurological symptoms [117].environmental factors and female sex hormones may influence risk, course and prognosis of MS. this theory is supported by the fact that prevalence of MS is two to three times higher in women than in men [118,119], and that there was a slower progression of MS in women who had given birth [120].Other studies have shown a positive effect of pregnancy on MS disease activity, possibly due to the high levels of circulating oestrogens during pregnancy [121][122][123][124][125].
Previous studies examining the association between cOcs and MS show conflicting results.effects of cOc exposure on the risk of developing MS were either positive [117,121], neutral [126] or even negative [127]. the age of first MS symptoms was significantly higher in women using a cOcP compared to non-users (onset 33 years vs 31 years) and with an increased duration of cOc use, the age of onset of MS increased proportionally [117].it has also been reported that cOcs have beneficial effects on the expanded Disability Status Scale (eDSS) progression in women with relapsing-onset MS [128,129] while associations in primary progressive MS were negative [112].cOc use did not modify the risk of a second attack or disability accrual in patients with early MS [116].

Potentially favourable effect on asthma
Asthma is a chronic inflammatory disease of the respiratory tract and it is characterised by variable and recurring obstructive symptoms such as coughing, wheezing and dyspnoea.Asthma incidence varies by sex over the life span [130].During early childhood, asthma is seen more often in boys than in girls.However, in puberty, the incidence, prevalence, severity and the impact on quality of life have been found to be higher in women than in men [131][132][133][134][135]. the mechanism of action behind this observation has not been established, but female sex hormones may play a significant role [133,136,137], since both oestrogens and progestins may stimulate smooth airway muscle function, inhibit the activities of t-helper 2 responses and influence inflammation and airway responsiveness [136,138].
the impact of use of cOc use on the risk and symptoms of asthma has been examined in several studies. in a 17-year population-based cohort study in women of reproductive age, previous, current and long-term use of any hormonal contraceptives were associated with a reduced risk of severe asthma symptoms compared to non-users [139].Other study results are conflicting and inconclusive.Some studies have reported no association between the use of cOcs and symptoms of asthma [140], while other studies have reported a decreased [132,141] or even an increased risk [141]. in women with a high BMi cOcs seem to reduce asthma symptoms.it has not been established whether eventual positive effects on asthma symptoms are caused by progestins, oestrogens, or both [138].

Less premenstrual attacks of porphyria
Porphyria is a mostly inherited liver disorder, building up porphyrins in the body and negatively affecting the skin and/or the nervous system.Acute porphyria presents with acute neurovisceral attacks, while cutaneous porphyria is characterised by photosensitive skin lesions [142,143].Oestrogens and progesterone stimulate the enzymes that produce porphyrins [144], explaining why many women with porphyria experience attacks either in the middle of the cycle, when a surge in oestrogen occurs before ovulation, or during the luteal phase of the cycle, when oestrogen and progesterone levels are high [143].Successful use of cOcs for the prevention of premenstrual attacks has been reported [145,146].

Health benefits of combined oral contraceptives related to malignancies
Almost all research on the relationship between cOc use and cancer risk relies on observational studies, either large prospective cohort studies or population-based case-control studies. in general, data from observational studies cannot definitively establish whether an exposure causes or prevents cancer or stimulates existing cancer.Overall, these studies have provided evidence that the risk of breast cancer and cervical cancer are increased in women who use oral contraceptives, whereas the risks of endometrial, ovarian, and colorectal cancers are reduced [147][148][149].
there is an ongoing discussion on the question whether cOcs carry a small increased risk of breast cancer (Bc), or just stimulate the growth of hormone sensitive Bc, which is outside the scope of this review.An analysis of data from more than 150,000 women who participated in 54 epidemiologic studies showed that, overall, cOc users had a slight (7%) increase in the relative risk of breast cancer compared with women who had never used cOc.women who were currently using a cOcP had a 24% increase in risk that was not related to the duration of use.Risk declined after use of cOc stopped, and no risk increase was evident by 10 years after use had stopped [150].women who have used cOcs for 5 or more years have a higher risk of cervical cancer compared to never-users.the longer a woman uses cOc, the greater the increase in her risk of cervical cancer and the risk has been found to decline over time after women stop using cOcs [151].

Less endometrial cancer
cancer of the endometrium is an oestrogen sensitive type of epithelial cancer.in the United States, endometrial cancer is the most common cancer of the female reproductive organs.the American cancer Society estimate that in 2022 approximately 65,950 new cases of endometrial cancer will be diagnosed in the United States, and that approximately 12,550 women will die from cancers of the uterine body [152].Hyperestrogenic states increase the risk of endometrial cancer with known risk factors being obesity and PcOS due to unopposed oestrogen in prolonged follicular phases.endometrial cancer affects mainly post-menopausal women.the average age of women diagnosed with endometrial cancer is 60. it is uncommon in women under the age of 45. women who have ever used cOcs have a lower risk of endometrial cancer than non-users of at least 30%, with a greater risk reduction the longer the cOcs were used [153].the protective effect persists for many years after a woman stops using cOcs [151,154,155].An analysis of women participating in the prospective NiH-AARP Diet and Health Study finds that the risk reduction was especially pronounced in long-time users of cOcPs, who were smokers, had obesity, or exercised rarely [154]. in the Nurses Health study, cOcs are associated with a lower endometrial cancer risk, independent of time since last use.Use of ee and second-generation progestins are more strongly and inversely associated with risk compared to older formulations [156]. in a Danish study the overall estimated absolute reduced risk of endometrial cancer in ever users of cOcs is 1.4 per 100,000 person-years, or approximately one endometrial cancer less for every 71,400 women of reproductive age who used cOcPs for one year.Use of cOc is estimated to prevent 25% of endometrial cancers in this population [157].

Less ovarian cancer
Ovarian cancer is often discovered at an advanced state and therefore has a poor prognosis.Ovarian cancer may originate from the ovaries or start its development in the fallopian tubes.
A review paper shows that, although ovarian cancer is relatively uncommon in cOc users, it has a high case fatality rate [158]. in this review, 22 case-control studies and three cohort studies are analysed, examining the relationship between cOc use and ovarian cancer.All but two of these studies show a protective effect of cOcs. in this analysis a 40-80% decrease in risk among cOc users is found, with protection beginning approximately one year after initiating use, with a 10-12% annual risk decrease for each year of use. in addition, protection persists until at least 15 to 20 years after discontinuation of cOcs [158,159] and the data also suggest that cOcs reduce the risk of ovarian cancer in women who are at high-risk for Bc due to BRcA1 or BRcA2 mutations [158][159][160][161].Other studies show that the relative risk of ovarian cancer for women who had used cOcs for at least 1 month, as compared with women who had never used them, is 0.6 (95%ci 0.4-0.9studies) [162][163][164].the protective effect of cOc use in these studies persisted for more than 10 years after cOcP use was discontinued and women who ever used cOcs have a 30% to 50% lower risk of ovarian cancer, compared to non-users.this protection is found to increase with the length of time cOcS are used [153].in a review of 55 studies including a random-effects meta-analysis of 24 case-control and cohort studies [163], a significant reduction in the ovarian cancer incidence is found in ever-users compared with never-users (OR 0.73, 95%ci 0.66-0.81).there was a significant duration-response relationship, with a reduction in incidence of more than 50% among women using cOcs for 10 or more years, continuing for up to 30 years after discontinuation.the lifetime reduction in ovarian cancer attributable to the use of cOcs is approximately 0.54% for a number-needed-to-treat of approximately 185 for a use period of 5 years [147].Altogether the data demonstrating protection against ovarian cancer by cOc use are very consistent.the incidence of mucinous tumours (12% of the total) seemed little affected by cOcs, but otherwise the proportional risk reduction did not vary much between different histological types [165].the mechanism by which cOcs exert this protective effect is thought to be related to the inhibition of follicular development and anovulation, thus resulting in a reduced frequency of 'injury' to the ovarian capsule [20].the data with respect to ovarian cancer are so compelling that the use of cOcs is even recommended to prevent ovarian cancer in women at high risk by virtue of their family history, carriers of the BRcA mutations, and nulliparity, even when contraception is not required [19].

Less colorectal cancer
there is growing epidemiologic evidence that cOcs protect women from developing colorectal cancer and cOc use is associated with a 15% to 20% lower risk of colorectal cancer [20,151,154,166]. in some studies, this protective effect appears to be directly proportional to duration of use, although this has not been a consistent finding.the mechanism of action of this protective effect is hypothesised to be related to reduced production of bile acids by altering the colon microbioma, by having a direct oestrogenic effect on colonic mucosa, or by having a tumour suppressor effect.in a systematic review [151], 12 cohorts and 17 case-control studies with a total of 15,790 colorectal cancers were included in the final analysis.the summary RR for ever versus never cOc use in this review is 0.82 (95%ci 0.76-0.88).Similar results are observed when comparing the longest duration of cOc use with the shortest duration (RR = 0.86, 95%ci 0.76-0.96).Furthermore, the results of a stratified analysis are comparable to those of the overall meta-analysis. in dose-response analysis, colorectal cancer is significantly reduced by cOc use (OR 0.86; 95%ci 0.79-0.95)[166].Significant inverse associations emerged in nonlinear models for the duration of cOc use and colorectal cancer (p = 0.001).in another study there were 4661 ever users with at least one cancer during 884,895 woman-years of observation and 2341 never users with at least one cancer during 388,505 woman-years of observation [154].ever use of cOcs was associated with a reduced colorectal incidence (incidence rate ratio, 0.81; 95%ci 0.66-0.99).Reproductive and menstrual factors were evaluated as surrogates for long-term hormonal exposure in the women's Health initiative Observational Study, a longitudinal cohort of 93,676 postmenopausal women (aged 50-79 years at enrolment) in which 1,149 incident cases of colorectal cancer occurred over a median follow-up of 11.9 years [167].Multivariable cox proportional hazards models that included established colorectal cancer risk factors were constructed to examine the association of colorectal cancer incidence with reproductive and menstrual factors.Parity and prior use of cOcs were associated with lower colorectal cancer risk in this cohort of postmenopausal women.Having had two children (vs nulliparous: hazard ratio (HR) 0.80, 95%ci 0.64-0.99)was inversely associated with colorectal cancer risk.compared with never users, ever use of cOcs was associated with lower colorectal cancer risk (HR 0.74, 95%ci 0.63-0.86),but no relationship was observed in this study for duration of cOc use (4 years vs 1 year: HR ¼ 0.94, 95%ci 0.67-1.32).the mechanism of action of the effect of cOc on colorectal cancer has not yet been established.

Summary and conclusions
Our review of the literature revealed a total of 21 health benefits of cOcPs, which were in previous reviews only presented in various subsets (table 1).considering that the most recent review was published in 2015 [27], we placed particular emphasis on recent publications, which constituted 40% of the total number of publications found. in summary, the use of cOcs has many important health benefits.the fact that we used only a few combined terms in our search, instead of 21 separate benefit terms, is a limitation, but we are confident about the current outcome on the 21 benefits identified.the cOc replaces the fluctuation of the natural menstrual cycle with stable levels of oestrogen and progestin except for a drop in hormone levels during the hormone free break of the cOcP cycle.the resulting cOcP ovarian quiescence and stable hormone levels lead to several of the observed health benefits that are caused by immediate effects of hormones such as endometrial thickness, bleeding, mood and ovarian cysts.the 21 health benefits observed are either related to the reproductive cycle or to non-reproductive general health benefits.Subjective health benefits noted by cOcP users are: less menstrual bleeding disorders including less anaemia and less toxic shock syndrome, less dysmenorrhoea, a favourable effect on migraine, less premenstrual syndrome (PMS), favourable effects on symptoms of Polycystic Ovary Syndrome (PcOS), less androgen related symptoms such as acne, hirsutism and voice changes, less perimenopausal symptoms and hypoestrogenism, less symptoms due to endometriosis and adenomyosis and less symptoms due to uterine fibroids.Some health benefits such as the treatment of heavy menstrual bleeding without organic cause (e.g., oestradiol valerate/dienogest), acne (e.g., ee/cyproterone acetate) and the premenstrual syndrome (e.g., ee/ DRSP) are approved as treatments by authorities (FDA, eMA).An overview of the non-contraceptive uses of cOcs and the literature is presented in the Supplement.For several diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), asthma and porphyria there is conflicting evidence and uncertain mechanisms of action, but the trend is the occurrence of less subjective symptoms and a more favourable course of the disease when using cOcs.Objective health benefits of the cOcP are: less ovarian cysts, a lower risk of ectopic pregnancy, a lower risk of pelvic inflammatory disease (PiD), less benign breast disease and a higher bone mass with less osteoporosis.Health benefits of cOcs related to cancer are the lower risks of endometrial cancer, ovarian cancer and colorectal cancer.
especially the more than 50% reduction of the incidence of ovarian cancer, lasting for many years after discontinuation of cOcP use, is a major advantage of cOc use and has led to the advice to use cOcs in cases of an increased risk of ovarian cancer, even when the contraceptive effect is not needed.
in conclusion, more attention should be paid by clinicians, researchers and the scientific and lay press to the short-and long-term health benefits of cOcs. to mitigate the current hormone fear, health care providers and media should inform and reassure present and potentially new cOcP users about the many advantages of this highly reliable and effective contraceptive method.

Table 1 .
reported health benefits of combined oral contraceptives (CoCs).