Hormonal and natural contraceptives: a review on efficacy and risks of different methods for an informed choice

Abstract The debate about contraception has become increasingly important as more and more people seek safe and effective contraception. More than 1 billion women of reproductive age worldwide need a method of family planning, and wellbeing, socio-economic status, culture, religion and more influence the reasons why a woman may ask for contraception. Different contraceptive methods exist, ranging from ‘natural methods’ (fertility awareness-based methods - FABMs) to barrier methods and hormonal contraceptives (HCs). Each method works on a different principle, with different effectiveness. FABMs and HCs are usually pitted against each other, although it’s difficult to really compare them. FABMs are a valid alternative for women who cannot or do not want to use hormone therapy, although they may have a high failure rate if not used appropriately and require specific training. HCs are commonly used to address various clinical situations, although concerns about their possible side effects are still widespread. However, many data show that the appropriate use of HC has a low rate of adverse events, mainly related to personal predisposition. The aim of this review is to summarize the information on the efficacy and safety of FABMs and HCs to help clinicians and women choose the best contraceptive method for their needs.


Introduction
In a world where society, economy and career are becoming more and more important in a person's life, a careful pregnancy plan is an especially important step for families.Throughout history, this issue has been more relevant than one might expect.In ancient times, the Romans and Egyptians tried to control their fertility and the number of children according to their parental project, developing the first examples of vaginal pessaries or vaginal sponges and condoms [1].Since then, women's needs have changed, and science has progressed.
In the twentieth century, the debate about birth control became central.Increased knowledge of female fertility made it possible to develop more reliable natural methods of contraception based on the body's cyclical changes.Meanwhile, in 1960, the first estroprogestin containing mestranol and norethynodrel was approved by the Food and Drug Administration (FDA) [2].The past 60 years have been a hotbed of ideas and innovation.Progress has been so rapid and fruitful that it has led to the development of many even safer and more versatile hormonal contraceptives (HCs) that can be used by an ever-growing population.In 2019, approximately 1.1 billion women of reproductive age worldwide will need a method of family planning, with nearly 50% of these women using HC methods [3].These numbers underscore the importance of contraception.
Contraceptive methods are extremely diverse, ranging from 'natural methods' (e.g. the Billings method) to barrier methods (e.g.condoms) and HCs.Each method has a different effectiveness and works on a different principle.Natural contraception is based on the ability to identify and avoid the fertile period of the cycle, favoring intercourse on the unfertile days of the month.HC, on the other hand, can inhibit a woman's fertility by inhibiting ovulation.However, too many people, including doctors, are still afraid to use hormonal methods because of possible side effects [4].
Situations around the world are very different, and women may need contraception for very different reasons.Well-being, socio-economic status, culture, religion -all of these and more influence the reasons why a woman may ask for contraception.The level of financial inequality in the world is staggering, with more than 60% of global household wealth in the hands of only about 1% of the world's population [5].The extreme poverty in third world countries and the difficulty many families have in providing for their offspring requires a safe and easily accessible method of contraception.Moreover, contraception is not just for families.Sexuality is a basic human value that is increasingly recognized in our society, but it should go hand in hand with sexual safety.Adolescents should be educated in this area and contraception should be freely available.We must also remember that contraception is sometimes necessary to protect a woman in difficult social situations, such as wars, and that sex is not always associated to love relationships or with a consensus between partners, but can also be a consequence of violence [6].Therefore, the contraceptive method must ensure the highest possible rate of success.In some social situations, contraception based on perfect control of the body's cyclical physiological changes may be inappropriate because it is too fallible.Knowledge of and access to HC should be improved so that most of the world's population can use safe contraception if they so wish.Natural methods of contraception and HCs are usually pitted against each other, even though it's difficult to really compare their effectiveness.On the contrary, barrier methods can be combined with other contraceptive methods, regardless of their effectiveness, because they also provide important protection against sexually transmitted infections [7].
In this historical panorama, the aim of this narrative review is to summarize the information on the efficacy of natural methods and HCs and to clarify that HCs are a safe and effective alternative for birth control, reviewing the literature on their most common side effects.Many data show that correct use of HC has a low rate of adverse events and that these are often related to personal predisposition.

Materials and methods
A systematic search on PubMed was performed to identify the most relevant publications on natural and hormonal contraceptive methods using a combination of the following terms: natural methods of contraception, fertility awareness-based methods (FABM), Billing ovulation method, symptothermal method, Pearl Index (PI), efficacy, estroprogestin, thromboembolic risk, metabolism, progestin, ethinylestradiol, failure rate, breast, endometrium, lipids, coagulation, depression, bone, weight, hyperandrogenism, menstrual irregularities.Relevant studies were also identified from review articles.
The search was limited to sources in English.All articles evaluating risks, benefits, and efficacy of natural and hormonal methods of contraception were included for this narrative review.

Natural methods for contraception
Contraception is not just hormonal.Different methods have been developed throughout history.Barrier methods are the only ones that protect against sexually transmitted infections, so they should be used regardless of the reason for family planning.However, they may fail to prevent unintended pregnancies, with a PI, defined as the number of unintended pregnancies per 100 women in the first year of using the method, ranging from 2.5 to 5.9, according to studies [8].
In addition to barrier methods, natural contraceptives are becoming more widely used and may have some advantages for women who cannot or do not want to use hormonal therapy.However, they have a high failure rate and require a lot of training before a woman can use them.In addition, not all women can use them because irregular menstrual cycles, such as during puberty, perimenopause, or polycystic ovary syndrome (PCOS), can lead to higher failure rates.Fertility window is generally large and can vary cycle to cycle and person to person.Virtually every day may be fertile, in particular if irregular cycles occur.The only completely safe method is abstinence.
Natural contraceptive methods include withdrawal and FABMs (such as calendar methods, Billings ovulation method, symptothermal method, fertility monitor).Withdrawal alone should be avoided because of the high failure rate.In a cohort of US women aged 15-24 years, 31% used withdrawal as a contraceptive method; of these, 21.4% experienced an unintended pregnancy, compared with 13.2% of women who used only other contraceptive methods [9].According to another study that collected data from many surveys, the withdrawal failure rate was 17.3% of users who became pregnant within a year of starting the method [10].The lack of studies makes it difficult to calculate PI for withdrawal.
FABM of family planning are defined by the World Health Organization (WHO) [11]: Fertility awareness-based methods of family planning involve identification of the fertile days of the menstrual cycle, whether by observing fertility signs such as cervical secretions and basal body temperature, or by monitoring cycle days.Fertility awareness-based methods can be used in combination with abstinence or barrier methods during the fertile time.[11] The calendar (or rhythm) method is the earliest form of contraception.It is based on past cycle lengths and calculates the estimated fertile days of the menstrual cycle.Obviously, given the high biological variability in the length of the menstrual cycle, particularly in some periods of a woman's life, this method is the least effective and is usually overcome [12].Another early approach was the basal body temperature method: it is based on the observation that the basal body temperature rises slightly after ovulation; therefore, intercourses are possible if the basal body temperature, measured on waking and before any activity, is elevated above baseline (i.e. the temperature of the first day of the menstrual cycle) for three consecutive days.This prolonged rise means that ovulation has already occurred [12].More precise FABMs have since been formulated, namely the Billing ovulation method and the symptothermal method.
Another natural method of contraception is the Lactational Amenorrhea Method (LAM).The definition of postpartum amenorrhea is a difficult issue.Recently, a Cochrane review suggested redefining lactational amenorrhea as no vaginal bleeding for at least 10 days after the end of postpartum bleeding [13].Breastfeeding causes a delay in the return of ovulation and menstruation due to the effects of prolactin on the pulsatile release of gonadotropin-releasing hormone [14].In breastfeeding women, the first menstrual period tends to be anovulatory [15]: with exclusive breastfeeding, ovulation returns in only 1-5% of women in the first 6 months after delivery [16].However, this percentage increases if breastfeeding is not regular or stops before six months postpartum [16].Anovulation in LAM is achieved when three criteria are fully met: (1) exclusive breastfeeding (no supplemental foods or liquids; at least 5 regular breastfeedings/day, including four during the day and one at night); (2) amenorrhea; (3) <6 months postpartum [17].The efficacy of LAM is >98% in the first 6 months postpartum [16].However, this method can only be temporary and should be replaced with another method after six months or earlier if the criteria are not fully met, and it can have a high failure rate due to the variability of ovulation return, so it will not be considered further in this review.

The Billing ovulation method
The Billing ovulation method is one of the most known FABM [18].This method is based on the recognition of the cervical mucus pattern as an indicator of the fertile and infertile phases of the cycle.With this method, couples avoid coitus during the fertile days, but they can have intercourse both before and after ovulation thanks to a better characterization of the fertile window.Women identify the beginning of the fertile (estrogenic) mucus and stop having intercourse; the last day of transparent, slippery mucus is called the 'peak day' and coincides with ovulation.The fourth morning after 'peak day' closes the fertile window [18].Billings and his wife also studied the use of this method in special situations, such as pre-menopause and lactation amenorrhea, and said that if fertile mucus does not occur due to an anovulatory cycle, women can safely have coitus as in the early days of the cycle for the entire cycle length [19].According to a 1981 WHO multicenter trial, 97% of women had an excellent or good understanding of the method after 3 cycles.After a 16-cycle trial, the PI was 2.8, considering only methodrelated pregnancies.Teaching-related pregnancies (i.e.pregnancies resulting from an error in applying the rules due to incorrect teaching or failure to learn the method correctly) were more frequent (PI: 3.5) [20].These results are ambiguous because they may encourage the use and improvement of FABM due to their quite good results in terms of PI, but in the meantime the PI are still too high compared to those of other contraceptive methods (i.e.hormonal contraceptives).Women should be instructed to consider that they may be at high risk of pregnancy during the period of learning the method, until they have learned it perfectly.

The symptothermal method
The symptothermal method combines calendar calculation, basal temperature shift and cervical mucus changes: coitus should be avoided when the calendar or cervical mucus suggests the onset of the fertile phase and can be resumed when another indication (basal body temperature or cervical mucus) suggests the end of the fertile phase.A prospective cohort study involving 900 women evaluated the efficacy of the symptothermal method over a 13-cycle observation period, which can be roughly compared to the PI (12-month observation period).The unintended pregnancy rate per 100 women per year (13 cycles) was 1.61, which decreased to 0.43 with accurate use of the symptothermal method (i.e. with total abstinence during the fertile period).After 13 cycles of method use, the overall satisfaction rate was 91.8%, with a discontinuation rate due to method dissatisfaction or difficulty of 9.2 per 100 women [21].Symptothermal and Billing ovulation methods for fertility control ensure that women can access sufficiently safe and free contraception using completely natural, nondrug methods.
Finally, new FABMs include hormonal monitoring to predict the timing of ovulation, as measurement of estrone and luteinizing hormone (LH) in urine [12].

Advantages and disadvantages of FABM
Natural birth control methods have some advantages and disadvantages.The main advantage is that they are completely free of charge for women, except for possible training sessions with experts or gynecologists and for electronic devices used for hormonal monitoring.This can be very important in third world countries.The use of natural methods is often underreported.When specific questions about natural methods were added to the standard contraceptive use questionnaire in Burkina Faso, there was a large increase in the percentage of women using contraception (58% vs. 38%).When specifically asked, 26% of women reported using natural methods (vs. 5% when no specific question was asked) [22].In addition, these methods can be considered safer, with no adverse events or complications since no medication is required.One study found that FABM users were generally similar to women using other contraceptive methods in terms of age, race/ethnicity, religion, education, and parity.The only difference was the percentage of married women (68% of FABM users vs. 44% of other contraceptive users) [23].
Data on the effectiveness of FABMs are extremely imprecise and variable due to the poor quality of the studies.Perfect-use contraception showed high success rates, but these data may suffer from excluding any deviation from perfect method use; instead, errors in method use in the general population may reflect an intrinsic difficulty of the method itself.Data in the general population usually show an acceptable success rate, but lower than any hormonal contraceptive method [8,12,24,25].Trussell and Grummer-Strawn reported a failure rate of 3.2% for correct and continuous use of the ovulation method, but this rose to 84.1% for imperfect use (similar to the proportion of women who become pregnant in the first year of targeted attempts), suggesting that this method is extremely unforgiving when used improperly [26].According to more recent data, the failure rate is 3.2% for perfect use of the Billing ovulation method and 0.4% for the perfect use of the symptothermal method [27].The clinician should be aware of the widespread use of FABMs, especially for calendar rhythm use, because these women are at higher risk of unwanted pregnancies if they are not fully aware of their fertility and accurate counseling is needed.Menstrual irregularities, which can occur at different stages of life (post-menarchal, pre-menarchal, PCOS), can greatly affect the efficacy of the methods, although some of these women can partially overcome the problem with methods that try to identify ovulation objectively (i.e.Billings ovulation method, symptothermal method, fertility monitors).In addition, changes in cervical mucus that begin during menstruation due to irregular and precocious ovulation may be obscured by blood flow, reducing the probability of success of the method.These methods should be combined with other pregnancy prevention strategies, such as condoms or withdrawal, to improve their effectiveness [19,23,28].In addition, accurate counseling should be provided, and women must be fully aware of how their fertility works and be strongly convinced to use the method perfectly.If there is a concomitant clinical situation, they should be informed about the possibility of using HCs, which combine fertility control with many clinical benefits (i.e.improvement of dysmenorrhea, cycle irregularities, clinical hyperandrogenism).Table 1 summarize benefits, risks and efficacy of different contraceptive methods.

Hormonal contraceptives: an ongoing story
After the first oral contraceptive containing mestranol and norethynodrel, called Enovid®, was introduced in 1960, many new molecules were developed, giving rise to different HCs.Both estroprogestin and progestin-only contraceptives have gradually evolved, and clinicians now have a wide range of alternatives to choose from, offering the possibility of individualized therapy and overcoming many of the risk factors that may have initially posed an obstacle to safe contraception.
CHCs contain progressively lower doses of estrogens and progestins, reducing the incidence of potential adverse events without sacrificing therapeutic benefits.

The history of progestins
The role of the progestin is to inhibit the peak of LH, to decrease ovarian response to follicle stimulating hormone (FSH), thus reducing estrogen secretion.In addition, progestins have local actions, making the uterine environment hostile to ovule fertilization: they have a direct negative effect on cervical mucus permeability, on sperm survival and transport to the fallopian tube.
All progestins have a progestogenic effect, i.e. the induction of characteristic changes in the estrogen-primed endometrium: these effects rely on the time and route of administration and on the dosage of the progestin.Moreover, any progestin has a specific dose necessary to inhibit ovulation.The balance between these effects causes some progestins to be usable as contraceptives and others not [29,30].
Progestins are classified in categories according to their structural origins.They have been divided in generations according to the time of first synthesis.Among those used in the field of HC, pregnanes (17-hydroxyprogesterone derivatives and 19-norprogesterone derivatives, i.e. chlormadinone acetate) and estranes (testosterone derivatives, i.e. norethindrone, norethynodrel, norethindrone acetate, and ethynodiol diacetate) are considered first generation progestins.Only few of these are still used in HC due to their androgenic properties that cause bothersome side effects, as oily skin, acne, and reduced levels of high density lipoproteins (HDL) [30].Secondgeneration progestins are called gonanes and derive from testosterone.This includes some of the most widely used progestins, such as levonorgestrel.Third generation include desogestrel, gestodene, norgestimate/norelgestromin, and etonogestrel.These molecules progressively lose the androgenic activity, acquiring a non-androgenic or an antiandrogenic effect.The newest progestins are the fourthgeneration ones, that include nonethylated estranes (i.e.dienogest and drospirenone, a spironolactone derivative) and 19-norprogesterones-derivatives pregnanes (i.e.nomegestrol acetate) [29][30][31].
The affinity of progestin for different receptors can be highly different.First, the effect on androgen receptor can vary.If oldest progestins maintain an androgenic activity (i.e.levonorgestrel), others (norgestimate, gestodene, and desogestrel) have a minimal or no androgenic activity, until those that have an anti-androgenic activity (dienogest, cyproterone acetate, drospirenone, nomegestrol acetate and chlormadinone acetate).The antiandrogenic effect on androgen receptors is maximum with cyproterone acetate; dienogest and drospirenone are approximately 40% and 30% of its potency [31,32].Progestins with androgenic effect can also modulate and counteract both the positive and negative metabolic effects of the estrogenic component.This capacity is lost from no-or anti-androgenic progestins: this means that both the positive effect of estrogens on carbohydrate and lipid metabolism, and their stimulatory effects on coagulation factors are at their maximal expression with these progestins [33].Progestins for HC should be carefully chosen according to the aim of the treatment for each patient.

Estrogens: new frontiers
The estrogenic component of combined hormonal contraceptives (CHCs) enhances contraceptive effectiveness by suppressing gonadotropins and provides better endometrial control.Moreover, it compensates the estrogenic deficiency induced by the inhibition of gonadotropin secretion.The first estrogen used for a pill was mestranol, the 3-methyl ether of ethinylestradiol (EE).Pharmacokinetally, 50 µg of oral mestranol is bioequivalent to 35 µg of EE; thus, considering that Enovid ® contained 150 µg of mestranol, it is easy to see that the estrogen doses used initially were much higher than now.The dose of mestranol was then reduced to 75 µg, until EE definitely replaced mestranol [34].
To decrease the cardiovascular risk of the CHC, new formulations with low doses of EE became available.The modern 'low-dose' CHCs contain less than 50 µg of EE; however, today virtually all CHCs have 15-35 µg of EE [35].This decrease was possible thanks to the availability of new progestins.
Due to its high bioavailability, EE have a strong impact on the hepatic metabolism, displaying a sustained biological activity on sex hormone binding globulin (SHBG), angiotensinogen, cortisol binding protein, coagulation factors and lipoproteins [36,37].More physiological forms of estrogens have recently been developed to overcome this effect on liver: the preparations with natural estrogens (17β − estradiol -E2 -, estradiol valerate and estetrol -E4) have negligible effects on carbohydrate and lipid metabolism and hemostasis, showing a safer profile than those containing EE [38,39].One of the main problems of natural estrogens is that they may cause a worse control of the endometrium, thus women experience irregular bleedings.However, a quadriphasic combination of E2 valerate/dienogest and a monophasic combination of 17β − E2/ nomegestrol acetate have been successfully marketed during the past decade, showing high tolerability, efficacy and safety [40,41].A new pill containing E4 and drospirenone has been recently marketed.E4 is a 'weak estrogen' naturally produced by human fetal liver.It activates the nuclear estrogen receptor α (ERα) as estradiol, but it has not effects on the membrane ERα [42].Its ability to uncouple nuclear and membrane activation and to act differently with a tissue specificity makes E4 a selective modulator, which can be called Native Estrogen with Selective Tissue Activity (NEST) [43]: it has an estrogenic activity on vagina, endometrium and bone and a very week estrogenic activity on breast [42,44,45].E4 has also a specific safety profile on coagulation thanks to a virtually neutral effect on liver function [46].This expands the range of people to whom CHCs can be safely prescribed.

Different options and routes of administrations
First, we need to distinguish between CHCs and progestin-only contraceptives: CHCs contain both estrogen and progestin and usually can ensure a better bleeding control.Then, another important distinction is between oral and non-oral contraceptives.
Oral CHCs are the most known and various.They can be mono-or multiphasic (i.e.different levels of hormones in different pills).The aim of multiphasic pills is to better mimic the natural human cycle and to minimize the bleeding problems in some formulations.The tolerance of monophasic and multiphasic pills is similar [47,48].Oral CHCs have a 28-day cycle.Traditionally they contain 21 pills, with 7 days of pill-free interval or placebo pills, even if the pill-free interval is progressively reduced to 4 or 2 days, up to a continuous regimen.During 7 free-pill days, ovarian activity may restart, most of all with very low dose pills, thus a delay in taking the first pills of the next cycle may be a cause of contraceptive failure [49].Prolonged or continuous regimens can improve compliance and ovulation control.
Non-oral CHCs have been developed to increase efficacy, compliance, and tolerance.Vaginal rings or transdermal patches have been commercially available for more than 15 years.Thanks to the higher bioavailability of hormones through non-oral routes of administration, it has been possible to lower steroid doses [50,51].
Oral-CHCs can have some limitations and not be recommended for some patients due to the possible side effects (i.e.deep venous thrombosis risk).This problem can be overcome thanks to other routes of administration (non-oral CHCs), to E4-containing CHCs and to progestin-only contraceptives, that all have less systemic effects.Some progestin-only pills (POPs) have a lower ovulation inhibition capacity than that obtained with CHCs containing the same progestin.However, they maintain the progestogenic effect on cervical mucus and sperm viability.On the contrary, desogestrel-and drospirenone-containing pills have a sufficient progestin dose to efficiently inhibit ovulation, also reducing the incidence of breakthrough bleedings that may occur with other POPs [52,53].Non-oral progestin-only contraceptives include injectable progestins, subdermal implant, and intrauterine devices (IUD); they were developed to avoid the one-per-day pill administration.Depot medroxyprogesterone acetate should be injected every three months, subdermal implants last three years, while IUDs should be replaced every three to five years, according to the type used.Thanks to their long life, they ensure greater compliance, with good safety profile and no effects on hemostatic parameters [54].

Efficacy and advantages of hormonal contraception
HC have represented an important step forward in medical history.It perfectly combines the need of family planning to the possibility to have medical advantages.
First, if correctly administered HCs can assure the highest efficacy for pregnancy control.A review by D. Mansour et al. in 2010 evidenced that long-acting HCs (as levonorgestrel IUD and subcutaneous implants) are the most effective in preventing pregnancy, with efficacy comparable only to that of female tubal sterilization [8].According to this review, the 1-year PI of implants (0-0.3) and levonorgestrel-IUD (0.09-0.11) was way lower than that of condom (2.5-5.9) and of natural contraceptive methods (3.8-20.4)[8].However, as already reported in this review, data about FABM are highly variable in the literature.According to some studies the PI of symptothermal method is very low, ranging from 1.61 when all cases are considered to 0.4 when only perfect use of the method is considered [21,27].Copper-IUDs have the second place in efficacy, with a PI ranging from 0.16 to 1.26.Short-acting HCs, both CHCs and POPs, have a higher PI, mainly due to the possibility of errors in administration (i.e.low compliance, malabsorption, drug interaction), but it is still very low and far from barrier and natural methods.Oral-CHCs PI ranges in general from 0 to 2.18; lower estrogen doses have a slightly higher failure rate than higher doses.Transdermal patch and vaginal ring have a PI that is intermediate between long-acting HCs and oral-HCs.According to other studies, POP showed a PI of 0.41 [8].A perfect-use pregnancy rate for oral HCs (including both Oral-CHCs and POPs) is estimated to be 0.3% [27].However, PI can be limited, showing only a 1-year time spot.The continued duration of use of the same contraceptive always declines the failure rate [55].In addition, there is more literature on hormonal contraceptives.This is because it's easier to conduct studies on them than on natural contraceptives.Studies of the effectiveness of individual FABMs are few and of low to moderate quality, with high variability in pregnancy rates among different FABMs and different studies.The variability in the populations studied precludes comparisons with other contraceptive methods.
As for continuation rate of contraceptive methods, this may reflect the satisfaction of the woman for the method itself.For continuation rate definition, only method-related reasons for discontinuation (changing methods or termination of contraceptive use while still at risk for unintended pregnancy) were considered, excluding all those women who discontinued because of pregnancy desire.According to the 2002 National Survey of Family Growth (NSFG), the method-related discontinuation rate for pills is 19.2% at 6 months and 31.9% at 12 months, while for FABM it is 40.1% at 6 months and 51.8% at 12 months.This survey did not distinguish between different types of pills and between different natural contraceptive methods [56].
An important project to remove existing barriers to access HC was performed in the last decade.The Contraceptive CHOICE Project (CHOICE) was a prospective cohort study that enrolled 9256 women in the St. Louis Missouri area providing free reversible contraception for 2 to 3 years.The aim was to increase the uptake of long-acting reversible contraception and decrease unintended pregnancy in the area.When the barriers of cost, access, and knowledge were removed, women chose the most effective and least user-dependent methods, with high satisfaction [57].Further analyses on CHOICE showed that, despite the removal of economic barriers, low socioeconomic status was associated with a higher incidence of unintended pregnancy (3.68/100 women-years vs 1.94/100 women-years), also after the adjustment for age, insurance status, education level, and history of unwanted pregnancies [58].
In general, many factors can affect the failure rate of a contraceptive method, and this is true also for HCs.According to a study by Bradley et al. age was the main responsible for changes in contraceptive failure and adolescents consistently experienced the highest failure rate.Moreover, failure rates, particularly for oral contraceptive pills, were substantially higher for women in the poorest quintile of population compared to those in the wealthiest households.Failure was generally more relevant for users of short-acting HCs compared to long-acting HCs.However, HCs were the safest contraceptive methods, with users of condom, withdrawal, or periodic abstinence experiencing the highest failure rates [10].A regular lifestyle and a stable sexual relationship favor the efficacy of contraceptive methods, particularly FABM, since they are related to the knowledge of one's own fertility and to the regular monitoring of one's own secretions and body changes.In addition, a regular menstrual cycle can help a woman to identify the fertile and non-fertile days of the month.Adolescents may be less likely to use contraception regularly for many reasons: they may have irregular menstrual cycles, they may experience more changes in their daily lives, they may have less stable relationships, and they may have occasional sexual relationships.All of these aspects can affect compliance with the chosen method of contraception.Therefore, a contraceptive method that is less dependent on daily compliance, such as an IUD, vaginal ring, or transdermal patch, may be the best choice for them.
HCs can add many advantages to the classic contraceptive effect (Table 1).They can be used as first or second line therapies for many different gynecological diseases.First, they can be successfully used to manage abnormal uterine bleedings (AUB) during fertile age once all significant structural causes are excluded.In an acute AUB, multidose oral-CHC or a multidose POP can be used; when acute scenario is resolved, levonorgestrel-IUD, oral-CHC (also with a continuous regimen) or POP and tranexamic acid can efficaciously treat AUB and reduce the risk of anemia [59].
When fibromyomas are the cause of AUB, HCs can be part of the medical approach.Oral-CHCs can control the bleeding associated to uterine fibromyomas, even if the effects may be limited and knowledge about the possibility to reduce their volume is limited [60].Progestins can induce endometrial atrophy but also reduce fibromyomas growth.Levonorgestrel-IUD both reduce bleeding and uterine volume in women with AUB and can be used as conservative treatment for women with fibromyomas [61].
Endometriosis is an estrogen-dependent disease.The treatment should be combined and tailored according to the symptoms and the diffusion of the lesions, but medical therapy can be part of the management of the symptoms and consists in the inhibition of ovulation and menstruation, and achievement of a stable steroid hormone milieu.Medical therapy should be conceived as a long-term treatment.Monophasic, low-dose, oral CHCs or POPs demonstrated overall safety, tolerability, good efficacy, and low cost; they generally are the best therapeutic compromise for chronic treatment.Norethisterone acetate and dienogest showed the highest efficacy.The aim is mainly pain relief [62].A continuous regimen can improve the effects on symptoms due to the absence of bleeding [63].
The stabilization of hormonal fluctuations obtained with HCs is helpful also to approach premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD), which refer to physical, cognitive, or affective symptoms that arise in the late luteal phase and remit with menses.Neuroactive metabolites of progesterone, in particular allopregnanolone, have been heavily implicated in the pathogenesis of PMDD.These metabolites rise sharply in the late luteal phase and interact with γ-aminobutyric acid (GABA) receptors.Women with PMDD showed to have an altered sensitivity to allopregnanolone compared to controls [64].However, the precise mechanism behind the onset of negative mood in these particularly susceptible women is still not completely clear.Selective serotonin reuptake inhibitors (SSRIs) are the gold standard for PMDD treatment, but CHCs have an important role in this field.Literature is sometimes inconsistent due to the wide variability of existing combinations, but it is generally accepted that drospirenone combined to EE is of great help to approach PMDD [65].
Both EE and different types of progestins may help to approach clinical signs of hyperandrogenism.CHCs are part of the first-line therapy for hyperandrogenism in polycystic ovary syndrome, eventually combined to anti-androgen drugs if total remission is not achieved [66].This effect is possible thanks to the induced state of rest of the ovaries, that consequently also decreases the secretion of androgens, to the increase in SHBG produced by EE, and to the eventual anti-androgenic effect of different progestins, that can also act on the skin 5α-reductase.Altogether, these effects cause an improvement of acne and hirsutism.This is true also for idiopathic hirsutism [67].
HCs can also be used to treat hormone deficiency in premature ovarian insufficiency (POI).The targets for hormone therapy, that includes HCs, mainly are improvement of cardiovascular, urogenital, bone and mental health as well as quality of life.There have been very few studies comparing different types of estrogen replacement for women with POI.However, if contraception is required, CHCs are a safe choice for women with POI that can partially supply the estrogen deficiency.Still few studies are available about the eventual more beneficial effects of combinations containing natural estrogens [68,69].When eating disorders and hypothalamic amenorrhea is present, HCs can be used in those women who desire for contraception.However, data about their effect on bone are conflicting; in general, they do not seem to improve bone density and should not be used solely for this purpose.A multidisciplinary approach to hypothalamic amenorrhea should be set up to restore ovulatory function, which includes behavior change, nutritional repletion (i.e.caloric intake, vitamin D supplement), stress reduction, and weight gain [70].
HCs can be also protective against some gynecological tumors, like endometrial and ovarian cancers, as better clarified later in the review [71,72].Literature is consistent also in showing a reduced risk for colorectal cancer among oral-CHC users [73].In conclusion, the medical advantages of using HCs are several; as seen, they are part of the conservative management of different diseases.This should be accurately explained to women who express concern about the possible interference of HCs with normal physiology [74].

The risk of side effects of hormonal contraception in everyday life
Although HCs have many advantages, the possible side effects should not be forgotten (Table 1).It is important to remember that HCs are drugs that can interact with the physiological mechanisms of the body.HCs may cause alterations in liver function leading to an increased risk of thromboembolic events and metabolic changes.In addition, some individuals may be more sensitive to hormone therapy because of the risk of breast cancer and mood depression.Therefore, these risks should be carefully evaluated and known so that the clinician can choose the right HC for each woman.
On the contrary, natural contraceptives have no side effects except for the risk of unwanted pregnancies in case of method-failure, as already mentioned in the first paragraph.

Thromboembolic risk with hormonal contraceptives
CHCs are associated with a slight increase in cardiovascular events since they can impair the hemostatic system.They can affect both arterial and venous system.This side effect has from the beginning raised concerns in general population and in scientists, who had the aim to explore all the causes of this increased risk to reduce as much as possible the incidence of venous thromboembolism (VTE) and arterial events.The main responsibility has been attributed to estrogen, but it has also been demonstrated that different progestins associated to the same dosage of estrogen cause different levels of risk.
The risk of arterial events (i.e.ischemic heard disease and stroke) is mainly reported for 'high-dose' CHCs (≥50 µg EE) [75].When low doses of EE are used this risk is not relevant [76].Moreover, the progestin used has its role, because arterial events are mainly reported when high doses of EE are associated with androgenic progestins [77].
The thromboembolic risk among healthy fertile women is rare, it ranges between 5 to 10 events per 10.000 women per year [78].However, CHCs, particularly oral combinations, can increase this risk.The incidence is still low even in CHC users (8-10 events per 10.000 women-years of exposure), surely less relevant than pregnancy and postpartum.Low dose oral-CHCs containing levonorgestrel and EE are usually considered the standard of comparison.A meta-analysis by Dragoman et al. indicated that oral-CHCs containing other progestins (i.e.drospirenone, desogestrel, cyproterone acetate, gestodene, or dienogest) with EE are associated to a 1.5-2.0-foldincreased risk of VTE compared to levonorgestrel-containing oral-CHC.EE + norgestimate cause a risk of VTE that is similar to that of EE + levonorgestrel [79].EE induces changes in the coagulation system, with an enhancement in pro-coagulation factors (fibrinogen and factors VII, VIII, IX, X, XII and XIII) and a reduction of inhibiting factors (protein S and antithrombin): this leads to a mild procoagulant effect [80].Anti-androgenic progestins, like levonorgestrel, can partially counteract the stimulatory effect of EE on coagulation, while new progestins with no-or anti-androgenic effects doesn't.Thus, this explains why some progestins with EE are associated to a higher VTE risk compared to levonorgestrel.Natural-occurring estrogens can ensure a more favorable cardiovascular risk profile: they have a lower impact on hepatic function.In particular, E2 + nomegestrol acetate have a favorable impact on hemostasis compared to other combinations [81].Data about the new combination with E4 and drospirenone are still scant, even if promising results on human studies are already available.The estrogenicity of E4 on liver and vascular system is considerably lower, thus E4/drospirenone caused lower changes than EE/drospirenone and similar or smaller changes than EE + levonorgestrel in procoagulant, anticoagulant, and fibrinolytic parameters [82,83].
In clinical practice, according to the WHO guidelines, history or acute events of VTE, stroke, ischemic heart disease, and complicated valvular heart disease are absolute contraindications for the use of CHC.However, an accurate anamnesis can drive the clinician in the correct choice.Family history of VTE in first-degree relatives is considered a condition where the advantages of using CHC generally outweigh the theoretical or proven risks (category 2 in the guidelines).If the suspicion is strong, it may prompt further investigation about hematological risk factors, such as thrombogenic mutations.If they are excluded, CHCs are not contraindicated, but the gynecologist may choose a low-impact CHC, such as very low doses of EE + levonorgestrel or natural estrogens, if no specific clinical conditions exist that require anti-androgen progestins [72].Obesity, age (>35 years), tobacco use, hypertension can increase the risk of VTE, as in general population; care must be taken when more risk factors are associated [72,84,85].
When CHCs are contraindicated for thromboembolic risk factors, POPs and other progestin-only contraceptives should be considered.Progestins alone do not cause significant hemostatic changes, thus the risk of VTE is similar to non-pregnant general population [86].According to the WHO guidelines on contraception, personal history of VTE, prolonged immobilization, known thrombogenic mutations are considered a category 2 of risk for the administration of systemic progestin-only contraceptives (POP and implant), thus they can be safely prescribed.They should be discontinued when acute events of VTE occur, regardless of the cause [72].They can also be administered in the post-partum period, also in breastfeeding women [72].

Lipid profile and metabolic changes during hormonal contraception
HCs can have an impact on different factors of metabolism.These effects are mainly due to the estrogenic component that can affect liver metabolism and vascular function, but different progestins can counteract or not this effect, as for the thromboembolic risk.
The major concern of many women when the gynecologist proposes the HC therapy is the body weight increase.It is very difficult to demonstrate a direct link between HC use and body weight increase, because many factors (i.e.genetic, environment, lifestyle) can affect this parameter.Many studies demonstrated a nonsignificant change of BMI, waist circumference and waist-tohip ratio during HC use [87].Nevertheless, the physician should advice the patient that changes in the lifestyle can avoid weight increase.This is of great importance also in PCOS women, where BMI and metabolic diseases may represent an important comorbidity.In PCOS, use of metformin is associated to less effects on BMI during CHC use [88,89].
Besides body weight, HCs can change the lipid profile of users.In general, according to the WHO guidelines, known dyslipidemias without other known cardiovascular risk factors do not contraindicate the use of any HC [72].The effects of HCs on lipid profile are heterogeneous.Estrogens increase very low-density lipoprotein (VLDL), high density lipoprotein (HDL) cholesterol and triglycerides, while they reduce low density lipoprotein (LDL) cholesterol.Progestins, in turn, do not significantly interfere in the LDL reduction induced by estrogens, but play a significant modulatory role in HDL and triglycerides levels promoted by estrogens.This role varies according to the androgenic activity of the progestin: those with androgenic activity (i.e.levonorgestrel) can counteract estrogen effect, thus causing a general stability of lipid plasma levels; no-or anti-androgenic progestins demonstrated a greater increase in HDL with a lower elevations in triglyceride levels compared to other formulations [90][91][92].Progestins alone do not affect lipids levels [80].The positive effect of anti-androgenic progestins containing CHCs on HDL and LDL levels should be considered as an additional beneficial effect of contraception, that may acquire importance in those women with higher risk of developing metabolic complications later in life (i.e.PCOS).In general, lipid profile should be monitored during contraception, particularly when high cardiovascular risk is present.If signs of deterioration appear, contraception can be reevaluated, with the possibility to switch to POPs or other low-impact HCs (i.e.IUD, implants) [93].Natural estrogens have a lower impact on liver metabolism, and they lose also that minimal effect that EE could have on lipid profile.This gives the gynecologist new and safer options when dyslipidemia or other metabolic alterations are present [94].The new E4/drospirenone combination represents another important and safe choice: its reduced effect on hemostatic parameters is associated to a quite totally neutral influence on liver function and lipid and carbohydrate metabolism [95].
Carbohydrate metabolism changes have been investigated, too.Many studies are performed in populations with altered carbohydrate metabolism, as PCOS women, and this may limit the results.According to a meta-analysis by Halperan et al. the use for 3 or more months of CHCs did not cause negative effects on glucose metabolism, as measured by the hyperinsulinemic euglycemic clamp, fasting glucose to insulin ratio, and homeostatic model assessments for insulin resistance (HOMA-IR) [96].However, the extreme heterogeneity of the results of the studies in literature makes it difficult to understand the real impact of CHCs on carbohydrate metabolism, mainly due to differences in age, BMI, and study design.It is possible that the dosage and type of the hormones used could not explain the differences, thus different CHCs didn't show to have side effects on carbohydrate metabolism [96,97].According to WHO guidelines, the presence of diabetes mellitus or PCOS with insulin resistance are not contraindications to the administration of different CHCs [72].

The bone and hormonal contraceptives
Strictly related to metabolism, bone mineral density represents another important thing to consider, also when prescribing hormonal therapies to very young girls.The fundamental role of estrogens in bone metabolism is already well-known: they stimulate periosteal bone apposition and inhibit endocortical resorption.Adolescence is a critical period for women's life: girls progressively acquire a solid bone mass until adult life [98].For this reason, in the last decades many studies addressed the problem of the eventual bone loss during HC therapy.
In adolescence, results on the effects of HCs were sometimes contradictory.Normally, in the early puberty low levels of estrogens stimulate bone accrual; later, higher concentrations of estrogen are needed to inhibit periosteal bone apposition.The peak bone mass is usually reached 3-4 years after menarche [99,100].Literature about the effects of CHCs in adolescence is scant, but it can't be ruled out that they can impair the achievement of the optimal peak bone mass.Estrogen dose may be associated with different effects: higher doses showed to be more detrimental, maybe because of a stronger inhibition of endogenous hormone production.However, it is still unclear whether this effect is EE-dose dependent.Similarly, it still has to be elucidated if the negative effect of CHCs on bone mass in young adolescents is reversible after discontinuation or if it may represent a long-term risk for osteoporosis [94,98].
As for adults, this negative effect seems to be absent.On the contrary, in some cases a positive effect of CHCs in perimenopausal women was demonstrated [101].Extended regimens with EE caused not significant changes on bone mass density compared to non-users, while a 21/7-day regimen caused a slight reduction of body mass density compared to controls and extended regimens [102].
In general, natural estrogens exert a neutral effect on metabolism.The effect on bone metabolism seem to be similar to that of EE-containing CHCs [103].Very little is known about new compounds containing E4.The study by Mawet et al. [104] did not detect any imbalances after treatment with E4 combined to drospirenone or levonorgestrel vs the combination EE/drospirenone in serum osteocalcin (a marker of bone formation) and C-telopeptide (a marker of bone degradation).Whether CHCs influence on fracture risk, regardless of the type and dose of estrogen used, cannot be determined from actual literature [105].
As for progestin-only contraceptives, they have not a direct effect on bone metabolism.Their possible detrimental effect may be due to an excessive suppression of endogenous estradiol levels.It has been postulated that estradiol levels between 30-50 pg/mL or higher during progestin-only contraception does not affect bone metabolism.On the contrary, lower levels of estradiol, that can be reached with DMPA injection, may cause bone loss and should be avoided [106].
In conclusion, WHO guidelines state that fertile women can use CHCs generally without restriction.The evidence is inconsistent on the question of whether CHCs may affect fracture risk.Moreover, CHCs may preserve bone mass in perimenopausal women [72].Some attention must be paid for adolescents during the first 3-4 years after menarche, when suppressed levels of endogenous estrogens may affect the achievement of the peak bone mass.

Breast cancer risk and other neoplasms
The estrogen/progestin combination is a factor that may increase the risk of breast cancer.A slightly increased risk was observed for hormonal replacement therapy; thus, it was hypothesized that also CHCs may represent a risk factor.However, the link between CHC and the increased risk of breast cancer showed to be very complex.Both estrogen and progesterone have stimulatory effect on breast cell proliferation, and this is true also for natural estrogens [107,108].
A Danish study on a very wide population was performed in 2017.They collected data from all fertile women (15-49 years old) who were taking CHCs, and they were followed for 10.9 years (19.6 million person-years).A little, time dependent increase in breast cancer development risk emerged (relative risk 1.20, 95% confidence interval -CI − 1.14-1.26).After discontinuation, this risk remained higher in those who took CHC for more than 5 years compared to never-users [109].These results agree with previous knowledge but give the important possibility to observe a very large population (1.8 million fertile women) with a long follow-up period, thus many biases and risk factors could be simultaneously investigated.This association has been evident since 1996, when the Collaborative Group analysis of HC and risk of breast cancer was published, declaring a relative risk for breast cancer in COC users of 1.24 (95% CI 1.15-1.33).Interestingly, it is more likely to observe localized breast cancers in association to HC [110].However, both this first study and the Danish study failed to infer whether CHC users were more likely to have their cancer detected earlier that would have been without ongoing therapy, which remains a notable open question.Some studies reported contradictory and more reassuring data, that complicate the topic, but in general the trend is to consider the possible slight increase of risk as a reality.This should not dissuade from prescribing CHCs: women who take this therapy are usually young or very young, thus the baseline risk is very low.Moreover, the risk tends to decrease over time after discontinuation [111].The sub-population of females with the BReast CAncer (BRCA) 1 or BRCA2 pathogenic variant also showed an increase of breast cancer risk during CHC usage compared to non-users and this risk remained higher after ten years from discontinuation [112].
The new molecule E4 may represent an important step forward in this field.As previously said, it can act as a NEST in the organism.However, still very little is present in literature about the combination of E4 and drospirenone.A study showed that E4 combined to progesterone or drospirenone did not promote breast cancer development or metastatic dissemination, possibly further limiting the very low risk of common CHCs [113].As for breast cancer survivors, any HC in contraindicated during breast cancer treatment, while it can be considered (category 3 of WHO guidelines) for past tumors with no evidence of current disease in the last 5 years [72].A family history of breast cancer, as for BRCA1/2 carriers, is not a contraindication (category 1), but a complete counseling to reassure women and a proper screening should be performed [72].
Progestins play a minor role in this risk, even if studies on progestin-only contraceptives are scant.A systematic review by Samson et al. in 2016 stated that progestin-only contraceptives do not increase the risk of breast cancer, even if future research is needed for a better insight [114].
On the contrary, endometrial and ovarian cancer are not of concern when thinking to HC, being this therapy protective also in BRCA1/2 carriers.Studies demonstrate a reduced risk for both endometrial and ovarian cancer during HC, except for the mucinous ovarian adenocarcinoma [71].A personal history of cancer is not a contraindication for HC (category 1) [72].As for cervical cancer, HC is considered a risk factor if used for more than 5 years, even if literature is scant.Barrier methods may reduce the risk thanks to human papilloma virus infection prevention [71].

Mood disorders and depression during hormonal contraception
In the last years, the interest and knowledge about mood disorders in adolescents and young adults increased.They are multifactorial diseases, where genes, environment, hormones, and life events are closely associated with each other.In this context, HCs have often been put in the spotlight as possible accomplices in the occurrence of mood disorders.We have seen that some gynecological diseases may be treated with HCs, so women that take them for medical reasons and see an improvement in their general conditions may be more prone to emphasize beneficial effects of them instead of adverse events.Those patients who take HCs just for contraceptive reasons may overestimate the side effects, thing that could influence their satisfaction.However, it is sure that HCs can affect brain function and structure, maybe increasing the risk of mood disorders in predisposed patients and, on the contrary, stabilizing hormonal fluctuations that cause PMS and PMDD, as already seen.
HCs cause a decrease of estrogen levels that might contribute to the onset of negative mood.However, EE could partially mimic E2 effects in the brain, which naturally has an anti-depressant effect [115].Instead, the most important contribution on behavior and mood comes from the progestin component, which can exert a direct effect on central nervous system (CNS) and its effect may vary according to its ability to act as agonists or antagonists on different steroid receptors.Progesterone can be converted in the brain to allopregnanolone, a neurosteroid that acts non-genomically in the CNS, altering neuronal excitability.Alterations of allopregnanolone levels can have a high impact on GABA receptors plasticity, affecting the control of emotions, mood, and behavior.The effects of different progestins on hormonal balance have been studied on women and animals.Levonorgestrel showed to reduce allopregnanolone levels in plasma and CNS, causing a general worsening of mood and anxious behavior.On the contrary, no-and anti-androgenic progestins, like drospirenone, nomegestrol acetate, and chlormadinone acetate, showed to have a positive effect on allopregnanolone and β-endorphin levels, also improving mood on human studies [116].However, the link between changes in neurosteroids levels and mood disorders is still not completely clear: they do not increase 'per se' the risk of depression, but they may represent an important risk factor in a subset of predisposed women.Adolescents might be more vulnerable to mood changes than adults during HC, mainly because of a particular brain sensitivity to internal and external stimuli [117].Moreover, another group with higher risk of mood disorders during HC includes those with ongoing or previous mental disorders [118].Thus, a proper anamnesis and counseling are essential when prescribing a HC and the clinician should not underestimate the mental health of women and the symptoms they refer.They can be safely prescribed, but a trustful relationship between patient and physician is essential, so that women feel comfortable in seeking medical attention if any new symptom appear and the physician can decide whether a switch to a different HC may be of help or not.In general, reducing hormonal fluctuations and the pill-free interval can help balancing the effects of hormones on brain.

Conclusions
Natural contraception aims to identify the fertile window to practice abstinence or use condoms in these days.On the contrary, HC offers the possibility of completely avoiding the fertile period for the whole month.HC generally has a higher efficacy and is easier for women to practice, regardless of their cultural and social status, whereas natural contraceptives need proper training to be effective.In addition, menstrual irregularities can affect the success rate of natural contraceptives.However, the use of FABMs helps a woman to learn how her body and fertility work and to gain body awareness, which gives her more control over her body.
Considering the differences in the rationale of natural and hormonal methods, a new definition can be adopted.HC cause the total blockade of fertility by inhibiting the normal functioning of the hypothalamic-pituitary-gonadal axis in a reversible way.Therefore, they can be fully considered as contraceptives.On the contrary, natural methods do not inhibit the natural fertility of the woman, but only aim to control and predict its cyclicity.Therefore, they can be called 'fertility control methods' instead of contraceptive methods.
Natural methods of fertility control can be used when a woman can accept less level of efficacy, but if her status or social condition does not allow her to become pregnant, it should not be considered as a choice for her.Doctors have the responsibility to offer contraceptive methods that can guarantee the full effectiveness to the woman, taking into account the extremely diverse situations that she has to deal with (e.g. economic problems, wars, violence).
HCs are very diverse and can be tailored to women's needs.Today, they are safer and low-risk and represent one of the most important achievements for women's personality and sexuality.The possibility of achieving an almost 100% success rate is a tremendous opportunity.In addition, better fertility control reduces the use of voluntary abortions, which can be an important ethical dilemma with multiple consequences for women's physical and mental health.HCs also have many clinical advantages that should always be considered when choosing the right contraceptive method for a woman.
The data regarding the high efficacy rate should encourage the conscious use of HC to satisfy the desire for a safe and effective method of family planning.However, since their introduction, most of the research has focused on the ability to inhibit ovulation and on contraceptive efficacy.Much remains to be discovered about the side effects and the precise mechanisms of each molecule and combination on different aspects of the organism (i.e.liver effects, thrombotic effects, mood control).Research should now focus on this new perspective in order to better personalize therapy and provide the best possible service to women.
The role of the gynecologist is essential, as a good knowledge of all the alternatives and their possible side effects will help guide the woman to the best choice for her.Personal predisposition to adverse events, if any, and the woman's social and economic needs should be assessed and properly addressed.

Table 1 .
efficacy, advantages, and disadvantages of different contraceptive methods.