Volume 5 - 2/2024, Short Review

Pre-print

Hormonal contraception and menopausal transition: a short review

DOI: doi.org/10.53260/grem.245026 | Citation

Tiziana Fidecicchi, Marisa Ardito, Matilde Giudetti, Stefano Luisi, Tommaso Simoncini

  • Tiziana Fidecicchi Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, Pisa 56126, Italy
  • Marisa Ardito Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, Pisa 56126, Italy
  • Matilde Giudetti Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, Pisa 56126, Italy
  • Stefano Luisi Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, Pisa 56126, Italy
  • Tommaso Simoncini CONTACT Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, Pisa 56126, Italy

Abstract

Background and purpose: As women enter perimenopause, their contraceptive needs evolve in line with hormonal changes. Clinicians should consider not only the prevention of unintended pregnancies, but also the potential relief of perimenopausal symptoms. This short review will summarize current knowledge regarding the different contraceptive options that should be considered when approaching a perimenopausal woman, with the goal of guiding the choice of treatment tailored to the woman's needs and the benefits and risks of each method.
Methods: A comprehensive literature search was conducted across multiple databases to identify relevant studies for this narrative review, with a focus on recent advancements and key themes in the field.
Discussion: Depending on the symptoms, combined hormonal contraceptives (CHCs) are usually preferred, as they offer the possibility of controlling abnormal bleeding, vasomotor symptoms, preventing endometrial hyperplasia, osteoporosis, and protecting against certain tumors. Natural estrogens offer even more possibilities in this group of women. If CHCs are contraindicated, progestin-only contraceptives can be used. However, although they retain contraceptive function and the ability to treat abnormal uterine bleeding, they are not useful for vasomotor symptoms and bone protection. Perimenopausal transition can also occur very early in women with premature ovarian insufficiency (POI), exposing them to a prolonged period of estrogen deprivation and potentially more serious long-term consequences; with appropriate contraceptive therapy, they can be followed up to the age of physiologic onset of menopause. Estrogen supplementation should always be considered in women with POI.
Conclusion: Contraception during the perimenopause should be tailored according to the symptoms that women present. Counseling is essential both before prescription of the contraceptive and for the decision of discontinuation, to correctly address women to postmenopausal hormone therapy.

Full article

Full Article

Introduction

Menopause is defined as the permanent cessation of menstrual cycles (more than 12 months since the last menstrual period) due to the loss of ovarian activity [1]. The average age of menopause is 50.5, but it can vary greatly from woman to woman [2]. Early menopause has been defined when it occurs between 40 and 45 years of age, while before 40 it is called premature ovarian insufficiency (POI) [3].

Menopause is not a sudden event: it is preceded by a period of variable length, characterized by hormonal fluctuations, when menstrual cycles are still present but often irregular and anovulatory, and when menopausal symptoms may begin [4]. According to the Stages of Reproductive Aging Workshop (STRAW) criteria, this transition period (called perimenopause) generally begins in a woman's 40s and is divided into early perimenopause (stage -2) and late perimenopause (stage -1) until the last menstrual period (stage 0) [5]. Irregular cycles in frequency, volume, or length are usually characteristic of early perimenopause due to possible anovulatory cycles, and in extreme cases the abnormal uterine bleeding (AUB) can cause severe anemia. During late perimenopause, menstrual periods become less frequent until the last menstrual period [4,5].

Besides irregular cycles, perimenopause may be associated to a myriad of symptoms, including vasomotor symptoms, mood changes and sleep disturbances [4]. The intensity of these symptoms can significantly impact a woman’s quality of life and daily functioning, particularly in a society where women are expected to continue their professional and personal responsibilities [6,7].

Moreover, women in perimenopause remain at risk of unintended pregnancies due to sporadic ovulation, and irregular menstrual cycles may complicate the prediction of the fertile windows. These pregnancies carry a higher risk of obstetric complications and of chromosomal abnormalities, contributing to elevating maternal and fetal morbidity and mortality rates [8].

Given these complexities, informed contraceptive choice during the menopause transition is essential for effective family planning and the management of perimenopausal symptoms. This paper explores the intersection of contraception and perimenopausal symptoms, offering insights into effective contraceptive options tailored for women undergoing the menopausal transition. The objective is to provide a comprehensive overview of risks, symptoms, and contraceptive choices to support informed decision-making and enhance overall well-being during this transitional phase.

Methods

This narrative review was conducted by systematically searching PubMed for relevant studies published between 2000 and 2024. Keywords included “hormonal contraception”, “menopause transition”, and “perimenopausal symptoms”. Articles were selected based on their relevance, methodological quality, and contribution to the field. The list of references of key articles were also screened for additional sources. Data were synthesized to highlight significant findings, emerging themes, and gaps in the current knowledge. This approach ensured a comprehensive and unbiased summary of the existing literature.

Why is there a need for contraception?

A decline in fertility, but high obstetric risks

After the age of 40, women usually experience a significant decline in fertility [9]. However, ovulation is still present and the irregular cycles, typical of perimenopause, can make it difficult to calculate when it will occur. On the one hand, the difficulties of conception in women who have not yet fulfilled their desire to become pregnant lead them to seek pregnancy with assisted reproduction techniques, which may not be immediately effective, and conception may occur late in their 40s. This is also a consequence of social changes and of educational and career aspirations that cause a tendency to postpone pregnancy and make it more difficult to achieve [10]. On the other hand, the difficulty in predicting ovulation may increase the risk of an unwanted pregnancy. A cross-sectional study in the United States found that 9.5% of pregnancies at older age (> 35 years of age) are unintended and that these women often have previous children [11].

This leads to many problems. First, the trend of voluntary abortions in women over 40 has been quite stable over the years compared to other age groups. In Italy, data from 2021 showed that 12.5% of induced abortions were requested by women over the age of 40 [12]. Second, pregnancies at advanced age carry many risks and complications for both mother and the fetus.

The definition of advanced maternal age has evolved in the last decades. If some years ago a 35-year-old woman was already considered a challenge in terms of risk of complications, nowadays the clinician is used to face women older than 40 (or even 50) years, also thanks to assisted reproduction techniques. Besides any ethical evaluation, it is important to remember that societal changes must face the biological reality. With ageing, the rate of spontaneous early or late miscarriage increases together with sterility rate [9]. The maternal mortality rate steadily increases with age, with women aged >45 having 4 times a higher risk compared to those between 35 and 44 years [8,13]. Women aged >45 years are also at increased risk of many medical conditions like myocardial infarction, cardiac arrest, pulmonary embolism, deep vein thrombosis, acute renal failure. Moreover, obstetric events such as gestational diabetes, gestational hypertension, preeclampsia, preterm labor, fetal growth restriction or fetal death are more likely to occur later in life than in young women [8]. Finally, there is a high risk of presenting fetuses with chromosomal abnormalities, such as Down’s syndrome [14].

The increased incidence of these adverse outcomes highlights the importance of effective counseling on contraception to mitigate the health risks associated with unintended pregnancies.

Perimenopausal symptoms: the quality of life

The main reason a woman seeks medical help is usually the onset of troublesome symptoms due to fluctuating hormone levels and the progressive decline in estrogen levels.

The most common are hot flashes and night sweats. According to global surveys, as many as 40% of women in Europe experience vasomotor symptoms during the menopausal years [6], which can last for several years. The intensity and frequency of vasomotor symptoms can vary widely, and the need for therapy usually depends on the intensity of the symptoms [6]. Considering the pathophysiology behind this symptom, which is mainly due to the progressive decline of estrogens and hormonal fluctuations, it can also occur in the perimenopausal period and greatly affect the quality of life of women [4,6].

As mentioned above, menstrual irregularities are also typical of the perimenopause, and the AUBs that characterize this period can be a real problem for these women, with serious consequences for their health and daily life [4,5]. Psychological symptoms may also be present during this phase. Hormonal fluctuations cause effects in the central nervous system, resulting in changes in neurotransmission, nerve cell-cell interactions, and hormone receptor expression. This may be associated with mood changes, anxiety, depression, and sleep disorders [15–17]. Women with a history of mood disorders during their reproductive years or with significant life stressors may be particularly vulnerable to these symptoms.

Some women may also start to suffer from vaginal dryness and dyspareunia during the perimenopause, which are part of the genitourinary syndrome of menopause [18]. This can have an impact also on quality of life and sexual function. Pain during sexual intercourse and decreased sexual function may occur early during the menopausal transition, while decreased sexual desire is often a symptom of the postmenopausal phase [19].

Therefore, effective management strategies during the menopausal transition are needed to limit symptoms and improve quality of life until menopause is reached, and menopausal hormone therapy can be initiated.

Contraceptive choice in perimenopause

According to actual Medical Eligibility criteria on contraception redacted by the World Health Organization (WHO) in 2015, there is no specific contraindication to any contraceptive method only according to age [20]. However, during the perimenopause more clinical problems may emerge, like hypertension, dyslipidemia, or other conditions, that must be carefully considered [4,21], and this may harden the choice for the right contraceptive due to the fear of possible side effects. In the last ten years contraceptive choice has widened, and even new safer options have emerged that may be particularly suitable for perimenopausal women when very low risk but in the meantime effective solutions are needed.

Available contraceptive options

Combined hormonal contraceptives (CHCs) include pills, transdermal patches, and vaginal rings. Many combinations of molecules are available. As for estrogens, ethinylestradiol (EE) is the most used. However, its impact on the liver may increase the risk of venous thromboembolism (VTE), and a change in the metabolism should be carefully evaluated in perimenopausal women [22–24], for whom the risk is already increased due to ageing compared to young adults. The impact on the liver and metabolism is due to the total “estrogenicity” of the combination, resulting higher when EE is associated to antiandrogenic progestins [25,26]. With new oral CHCs containing natural estrogens, like 17b-estradiol, estradiol valerate, and estetrol, the thromboembolic risk is greatly reduced thanks to the lower or potentially absent effect on the liver and thus on the synthesis of coagulation factors [23,27–29].

When estrogens are contraindicated, progestin-only methods may be a viable alternative [30]. They comprehend progestin-only pills (POPs), injectables like depot medroxyprogesterone acetate (DMPA), subdermal implants like levonorgestrel or etonogestrel, and levonorgestrel-containing intrauterine systems (LNG-IUS). DMPA, implants and LNG-IUS are long-acting reversible contraceptives that are ideal for women with adherence issues [31]. All these methods are effective to prevent pregnancies, but they do not address estrogen-deficient symptoms.

How to choose the right contraceptive during the menopausal transition

The choice of contraceptive method must be personalized according to the needs and characteristics of women. Comprehensive counseling is essential to thoroughly inform the patient about the efficacy, side effects, and potential implications of each method. Common misconceptions and concerns should be addressed, and evidence-based information can help women alleviate these concerns and make the decision easier. In addition, women may be able to better cope with the menopausal transition by discussing the symptoms and signs that may accompany this transition [32].

Three considerations should guide the choice: what are the symptoms we want to treat; what are the extra-contraceptive benefits we want to achieve; and what are the comorbidities and risks that may limit the choice.

Examining the symptoms of distress to help choose

Perimenopausal women may experience a wide range of symptoms in various combinations [4]. The clinician's role is to identify which are the most bothersome and to treat them.

In general, CHCs are most commonly used to treat menopausal symptoms, which are mainly due to the progressive loss of estrogen. Oral CHCs are the most flexible option because they are available in cyclic, extended or continuous regimens. The shortened or absent hormone-free interval help reduce vasomotor symptoms, menstrual migraines, and AUBs [33]. They also provide the opportunity to use natural estrogens to reduce EE-related health risks [29], a useful option for this group of women.

Vaginal rings and transdermal patches can also be used in a cyclic or continuous regimen and are effective in reducing estrogen withdrawal symptoms. They avoid the first pass through the liver and therefore have potentially fewer side effects, although the data are controversial, especially for the transdermal patch [34]. Natural estrogens cannot be used in non-oral combinations, so these always contain EE.

If we want to address vasomotor symptoms, we need to use CHCs and, if necessary, estrogens can also be added during the placebo days. One study showed that oral CHCs adding estrogen during the placebo days significantly reduced vasomotor symptoms, depression, and sexual dysfunction compared to placebo pills [35].

Oral formulations may be preferable during the perimenopause thanks to the possibility of modulating the estrogenic part with lower doses of EE (which are sometimes insufficient to control symptoms) and, above all, with natural estrogens. Natural estrogens are safe and effective and should be the first choice in women aged >40 [23,27–29]. Quadriphasic combinations containing dienogest have low levels of estrogens even during the progestin-free interval [27].

Migraines can also be a problem during the perimenopause, especially for women with menstrual migraines [36]. Again, CHCs may be an option, and extended or continuous regimens should be preferred to reduce hormonal fluctuations. For women with migraine who need contraception or who experience estrogen withdrawal headaches, the European Headache Federation (EHF) and the European Society of Contraception and Reproductive Health (ESCRH) recommend oral CHCs [37]. However, attention should be paid to migraine with aura, which is an absolute contraindication for the use of CHC due to the increased risk of ischemic stroke. In this case, a POP may be used to stabilize hormone levels as much as possible, although it may not have an effect on estrogen-withdrawal symptoms [20]. Moreover, migraine without aura should be carefully evaluated: cardiovascular risk factors must be assessed, and if during CHC administration migraine characteristics change, this may represent a reason for discontinuation of estrogen-containing contraceptives [20,36,38].

If the clinician needs to address AUBs in the perimenopause, the choices are wider [39,40]. Both CHCs and progestin-only methods can be used. Continuous oral contraceptives are effective in reducing blood loss, especially oral formulations. Oral CHCs containing estradiol and dienogest are indicated to reduce heavy menstrual bleeding [41]. POPs can generally be used without specific contraindications. The drospirenone-only contraceptive pill offers an improved bleeding pattern with a higher degree of predictability thanks to the hormone-free interval [42]. DMPA injection is associated with high rates of amenorrhea, although the risk of bone mineral density (BMD) loss [43] may make it less suitable for women over the age of 45. The LNG-IUS is often the first choice for AUBs [44], even when they are associated with endometrial hyperplasia [45]. In addition, when menopause finally occurs, they can be left in place for endometrial protection and combined with transdermal or oral estrogens for menopause replacement therapy [46]. Today, the 52-mg LNG-IUS, which is indicated for heavy menstrual bleeding and dysmenorrhea, is considered safe for endometrial protection during estrogen replacement therapy and can be used to combine contraceptive efficacy, endometrial protection and the treatment of menopausal symptoms, with very low cardiovascular risk [47]. On the contrary, copper intrauterine device and etonogestrel implants can cause unpredictable and heavy menstrual bleeding, making them less suitable during the perimenopause [48].

Menopausal transition can be a period when sexual dysfunction may be distressing, so it is important to address these symptoms during counseling. CHC can positively influence sexuality by reducing pregnancy fears and alleviating gynecological conditions [49]. However, its effects on sexual arousal and dyspareunia are complex and influenced by various factors. In cases of hypoandrogenism or sexual interest disorders, CHC with less antiandrogenic progestins or natural estrogens is the recommended treatment [50]. Additionally, natural estrogens or vaginal rings can help alleviate issues like dyspareunia [51]. Once prescribed, an ongoing open dialogue and trust between the woman and her healthcare provider is essential to assess whether the therapy is improving or worsening the woman's sexual function.

Think of other non-contraceptive benefits

Although symptoms should be the primary consideration in choosing the right contraceptive, the possibility of other non-contraceptive benefits must be considered.

First, the menopausal transition is the moment when the risk of osteoporosis starts to increase, thus, this always has to be considered when choosing the contraceptive method and, later, the menopause hormone therapy. Commonly used low-dose CHCs do not significantly affect the BMD of adult women [52,53] and, in perimenopause, they have positive results in preventing BMD loss, an effect that seems to be progesterone-independent [52,53]. However, data on the risk of fracture are lacking and not conclusive [54,55]. Less data is available regarding progestins and bone. POPs have a minimal impact on BMD [56], while LNG-IUS mechanism of action have no correlations with bone metabolism. On the contrary, DMPA induce an important hypoestrogenic state that may cause the loss of BMD [43], thus it should be avoided in women aged >45.

Perimenopause and menopause also represent a period when the oncological risk increases. In this panorama, it is important to remember that CHCs significantly reduce the risk of ovarian and endometrial cancer, a protective effect that increases with longer use and lasts decades after discontinuation [57]. Ovarian cancer risk is 50% lower after 15 years of use of CHCs [58]. Moreover, they are a feasible option also for BReast CAncer gene 1 and 2 (BRCA1/2) mutation carriers, particularly to reduce ovarian cancer risk [59]. CHCs are also associated with a reduced risk of extra-gynecological cancers, like colorectal one [60]. The role of progestin-only methods on ovarian and colorectal cancer has been less studied, but LNG-IUS is known to reduce the risk of endometrial and cervical cancer [61,62].

Think of the comorbidities and risks

When a hormonal contraceptive is prescribed, a thorough medical evaluation is necessary to weigh the benefits and risks of each choice. Some risk factors, such as cardiovascular disease, VTE, and oncologic risk, are age-related and are more important in perimenopausal women than in young adults. First, smoking is a major risk factor that may contraindicate the use of CHCs after the age of 35 [20]. Similarly, obesity, arterial hypertension and diabetes mellitus increase the risk of cardiovascular and thrombotic events [21].

The definition of cardiovascular risk in perimenopause and menopause should also consider women-specific risk factors, such as obstetric complications during pregnancy (e.g., preeclampsia, preterm labor, gestational diabetes mellitus) and endocrine and gynecological conditions (e.g., polycystic ovary syndrome, hypogonadotropic hypogonadism, endometriosis) [63].

The risk of VTE increases with age. It is a multifactorial disease, and its annual incidence is more than doubled at the age of 50 as compared to the age of 25 [64]. CHCs increase this risk two to three times compared to nonusers, age-dependently [65]. This risk depends on both, the dose of estrogen and the type of progestin. Lower doses of estrogen reduce the risk of VTE and arterial thromboembolic events [66,67]. In addition, the overall "estrogenicity" of the combination is important in assessing the effect of CHC on the liver [25,26].

Levonorgestrel, an androgenic progestin, with EE is associated with a 50% lower risk of VTE compared to third-generation progestins with EE [68]. However, new oral CHCs containing natural estrogens (a quadriphasic preparation containing estradiol valerate and dienogest, a 24/4 regimen preparation containing estradiol and nomegestrol acetate and a 24/4 regimen preparation containing estetrol and drospirenone) offer a safe alternative. Their VTE risk is very low, and they may be a safer alternative for women over 40. Evidence in this specific age group is still limited, particularly for estetrol-containing pills, however, because of their theoretical safety benefits demonstrated in the general population, they should be recommended as a first choice for perimenopausal women. The WHO medical eligibility criteria of 2015 still do not differentiate between EE and natural estrogens, but recent studies have found that the risk of these combinations is equal or lower of that of EE + levonorgestrel [20].

When high cardiovascular and VTE risk is present, progestin-only methods can be safely used [20].

CHCs are also associated with an increased risk of breast cancer, especially with long-term use. This risk decreases after discontinuation of therapy [69,70]. Hyperplasia with atypia and breast cancer are absolute contraindications to any hormonal contraception [20,71]. This risk is similar for POPs [72] and with LNG-IUS [73]. In this case, copper intrauterine devices are the only available option [20].

Hormonal contraception should also be avoided in patients with stromal ovarian cancer and follicular lymphoma [74].

When to stop contraception? The switch to menopause hormone therapy

It is generally recommended to discontinue hormonal contraception at the average age of menopause or when it is medically confirmed that a woman has reached menopause. Discontinuation may be followed by an observation period to see if spontaneous cycles return, and if they do not, menopausal hormone therapy may be started. CHCs suppress both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, so they should be discontinued to assess whether menopause has occurred. In contrast, with POPs, plasma FSH levels can be measured before discontinuing the method for the diagnosis of menopause [33].

However, if women have no contraindications, are at low cardiovascular risk, and have not yet reached menopause, the healthcare provider may consider continuing contraceptive therapy with periodic reassessment of menopausal symptoms and cardiovascular risk. The goal is to provide a seamless transition from contraception to replacement therapy to ensure continuous management of menopausal symptoms while avoiding the risk of pregnancy.

Premature ovarian failure: a similar but different situation

POI can be challenging. Hormone therapy is essential because these women are at high risk for long-term estrogen deficiency consequences. Age at natural menopause is associated with nonfatal cardiovascular disease, coronary heart disease, and stroke, and women <40 years of age have a significantly higher risk of developing these problems in their lifetime than women who reach menopause at the average age (50.5 years) [75]. POI also causes accelerated shortening of leukocyte telomere length, a marker of cellular aging and genomic instability, contributing to increased cardiovascular risk [76]. Osteoporosis must also be considered in women with POI because it may start earlier [77].

Symptoms characterizing POI are the same as those usually occurring during spontaneous menopause transition, thus hormonal contraception may help women with POI to address them [78]. Moreover, as for menopausal transition, these women may experience unwanted pregnancies. A 50-60% of women with amenorrhea, high gonadotropin levels and normal karyotype have fluctuating ovarian hormone levels that can cause sporadic ovulation: 11-46% of women may ovulate in a 6-month period. Thus, 5-10% of women may conceive spontaneously and unexpectedly after diagnosis, with a pregnancy loss rate similar to that observed in the normal age-matched population (20%) [79].

When treating POI, both the desire for pregnancy and the risk of spontaneous pregnancy should always be evaluated [79]. This will guide the choice between hormonal contraception and menopausal hormone therapy. Regardless of the choice, estrogen supplementation is essential for these women, and the dose of the used estrogen should be age-appropriate, being higher for younger women. If pregnancy is not an option for the woman, CHCs can be used to avoid the risk, with good results in relieving symptoms and preventing long-term consequences. However, in very young girls, CHCs may not be sufficient for bone development, reducing the possibility of reaching peak bone mass [80].

Thus, the choice between contraceptives and hormone replacement therapy should be patient-oriented [81].

Conclusions

The transition to menopause presents several challenges that require an informed and personalized approach to choose the right hormonal contraceptive. The goal is to ensure both effective pregnancy control and management of perimenopausal symptoms. In general, CHCs offer a versatile option and can counteract all symptoms due to estrogen deficiency. The advent of natural estrogens has further increased the potential for prescribing CHCs due to their reduced thromboembolic risk and favorable metabolic profile compared to classic EE-based options. Natural estrogens should be considered the first choice in perimenopause, also replacing the classic EE + levonorgestrel combination, which has always been considered the reference point for low risk.

A balance of risks and benefits should be performed before prescribing hormonal contraceptives, and if estrogens turn out to be contraindicated, progestin-only methods may still be useful to improve some symptoms, such as AUBs, with very low risks.

In summary, the perimenopausal transition requires a tailored approach for contraception that addresses both contraceptive needs and symptom management to improve a woman's quality of life. Ongoing reassessment and patient-specific adjustments are essential to effectively manage this complex period.

Disclosures

The authors have no conflicts of interest to disclose.

Funding

No funding was necessary for this paper.

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Citation: Fidecicchi T.,Ardito M.,Giudetti M.,Luisi S.,Simoncini T., Hormonal contraception and menopausal transition: a short review, GREM Gynecological and Reproductive Endocrinology & Metabolism (2024); doi: 10.53260/grem.245026

Published: November 19, 2024