by Sara Gottfried, MD and Kirti Salunkhe, MD
Perimenopause refers to the years of hormonal upheaval before the final menstrual period. It can begin in a woman’s mid-30s or 40s. However, perimenopause is a state of body and mind, not a chronological destination. It begins with dropping progesterone levels and ends with dropping estrogen levels. For some women, it is a time when perimenopausal symptoms begin in earnest. Mood becomes unpredictable, weight climbs, and energy wanes—and most commonly, women experience a conflation of all three. Other women may feel free of the hormonal straitjacket of the fertile years and start speaking the truth about what they want and need. Which camp you join may be determined by how you prepare to navigate these subtle, and at times dramatic, hormonal changes in your patients.
Here’s the bottom line: Perimenopausal symptoms are not well understood by most women, and certainly not by their mainstream physicians. Most women don’t realize that perimenopause is much rockier and more difficult than menopause, because hormones fluctuate month to month, sometimes mildly and sometimes fiercely. Perimenopausal symptoms are very common if you know what to look for and how to discuss potential issues with patients.
Younger women sometimes figure menopause is some future cliff they’ll fall from, around age 50 or so, in the distant future. Not so. Our bodies have been preparing for this cliff for years, and it will pay future dividends for you to understand the “perfect storm” of perimenopausal hormone imbalances. Common perimenopausal symptoms that can begin in one’s late thirties include more frequent periods, worsening PMS, deteriorating libido, and growing waistline. (Note that a typical period frequency can decrease from an average of every 28 days down to 21 days, and if bleeding occurs more frequently than every 21 days, it requires gynecologic investigation.) Your patients may find that old methods of coping (occasional exercise, yoga a few days per week, chocolate, a glass of wine most nights) don’t seem to work as well for perimenopausal symptoms. Metabolism becomes less forgiving. Women may feel more stressed out. Sleep erodes. Amygdala hijack can occur almost daily—meaning the “reptilian,” or lower, brain, not the rational being, takes over, and overreaction may become the norm. Sometimes your patients’ spouses or partners feel like the enemy.
Perimenopause doesn’t have one particular hormonal root cause. Rather, it’s an expression of hormonal interdependence. In other words, our patients experience the interplay of their major hormones at a time of great neuroendocrine chaos, and this generates for some women substantial perimenopausal symptoms. This life stage need not be a death march through middle age; perimenopause is simply a period of biological rough waters that can be navigated optimally with a smart captain at the helm of the ship. That’s where you come in.
This process starts with understanding what’s happening physiologically. Together, we will perform root-cause analysis as we do for any Functional Medicine evaluation and implement needle-moving changes, rather than settle for the superficial symptom maskers that mainstream medicine may have on offer.
Are you in?
There are several significant milestones that occur during a woman’s lifespan. Two of these milestones, puberty and perimenopause, reflect substantial changes that affect a woman’s physical, psychological, social, and physiological health. Puberty is the process of physical maturation for reproduction that occurs between ages 10–14 years in females.1 Perimenopause is the period leading up to and immediately following menopause and is increasingly being known as the menopausal transition (MT).2,3 Puberty and perimenopause signify the beginning and the end of a woman’s reproductive life cycle and have been linked to numerous alterations in the hypothalamic-pituitary-gonadal (HPG) and the hypothalamus-pituitary-adrenal (HPA) axes.4 A summary comparing the changes noted in the HPG axis during puberty and perimenopause is seen below (Table 1):4
Table 1. Summary comparing hormonal changes in puberty and perimenopause in HPG axis
With an aging population, there is a proportionate increase in the number of older women. This leads to concurrent increases in associated chronic diseases and disabilities. These unwanted health issues are particularly evident during perimenopause and/or the MT (~ age 50 onward) and are thought to be linked to the drop in estrogen levels and progressive loss of ovarian function that occurs at this time.
In recent years, the effects of genetic and environmental factors have also been a focus regarding the menopausal transition. Evidence has shown that familial and genetic factors may play a role with estimates of heritability ranging from 30-80%.5 One European genomewide association study of nearly 3,000 women identified 6 single nucleotide polymorphisms in 3 loci on chromosomes 13, 19, and 20 associated with age at natural menopause, and a Dutch study indicated that polymorphisms of an estrogen receptor gene were linked to earlier surgical and natural menopause.6,7 Further investigation using the same sample of the participants from these two studies indicated that the hormone metabolism and biosynthesis pathways were associated with age at natural menopause and that genes involved in premature ovarian failure were also significantly associated with age at menopause.8 A recent study has shown that two single nucleotide polymorphisms of the tumor necrosis factor (TNF) receptor family have also been shown to be significantly associated with age at natural menopause.9
Emerging evidence suggests there may be links between environmental exposures and their influence on the timing of perimenopause.5,10 Endocrine-disrupting chemicals (EDCs) are known to adversely affect human health, and data from a recent study evaluated the effects of 111 EDCs on 31,000 women who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999-2008.11 Eligible participants in this cross-sectional analysis included: menopausal women >30 years of age; not currently pregnant, breastfeeding, using hormonal contraception; no history of bilateral oophorectomy or hysterectomy. Exposure was defined by serum lipid and urine creatinine-adjusted measures of EDCs, and EDCs were stratified into long (> 1 year), short, and unknown half-lives; principle analyses were performed on those with long half-lives as well as phthalates, known reproductive toxicants. Of the initial 111 EDCs evaluated, the researchers found 15 chemicals that showed significant associations in any of the threshold or dose-response analyses to earlier age at menopause.10 The authors note that the 15 chemicals included nine PCBs, three pesticides, a furan, and two phthalates. Fourteen of the 15 EDCs examined showed evidence of a dose-response relationship in at least one analysis, suggesting that increasing levels of environmental exposures of these chemicals could adversely affect ovarian function.10 The observed magnitudes of effect of these 15 chemicals, ranging from 1.9 to 3.8 years earlier menopause, are larger than those previously documented for primary exposure to tobacco smoke, which has been shown in prior NHANES studies to associate with 0.8 to 1.4 years earlier menopause.10
The neuroendocrine system is responsible for significant hormonal changes that occur in the HPG axis. These changes are most notable during both puberty and perimenopause, primarily due to major changes occurring in the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) at those times. LH and FSH regulate ovarian follicle growth and ovulation, and estradiol, the most abundant form of endogenous estrogen.1,12-14 During a woman’s life, levels of estradiol begin to increase from puberty till menarche (~ 12 years). After menarche until perimenopause, estradiol levels remain fairly stable; erratic and fluctuating levels mark the onset of perimenopause. During menopause, estradiol levels decline, receding to levels similar to those of childhood (Figure 1).
Another set of endocrine changes, involving the HPA axis and cortisol, also occur during puberty and perimenopause.1 Emerging data have indicated girls experience increased cortisol production during puberty.1,15 Cortisol is the major hormonal output of the HPA system, and its levels vary throughout the day. This variation is based on circadian rhythms (higher morning levels and lower evening levels) and experiences of stress or challenge (cortisol reactivity).16 Studies show elevated cortisol levels during the transition from perimenopause to menopause.17,18
Aging follicles become more resistant to gonadotropin stimulation, and this leads to increased levels of FSH and LH. Raised FSH and LH levels subsequently result in increased estrone and decreased estradiol levels.2,3 Other pathophysiological effects seen during the MT include declines in dehydroepiandrosterone (DHEAS) and high-density lipoprotein (HDL) as well as increases in total cholesterol, low-density lipoprotein (LDL), and apolipoprotein B levels.2,3,19
Although not in the same abundance as men, women also produce the androgen hormone testosterone in their ovaries and adrenal glands. In healthy women during the reproductive years, normal levels of testosterone (15 -70 ng/dL) have multiple functions including supporting bone growth and strength, promoting cognitive health, and maintaining sex drive or libido.20-22 There is a natural reduction in testosterone levels as a woman ages due to lessening of ovarian production, and evidence is still emerging regarding treatment of low testosterone in the older female. In 2014, a task force appointed by the Endocrine Society, American Congress of Obstetricians and Gynecologists (ACOG), American Society for Reproductive Medicine (ASRM), European Society of Endocrinology (ESE), and International Menopause Society (IMS) concluded that it was inadvisable to treat low testosterone in women due to a lack of research; however, they noted an exception in those women with hypoactive sexual desire disorder (HSDD).21,23 Alternative therapies to relieve the symptoms of low testosterone that may be considered include:23
- Sex therapy
- Stress management
- Healthy dietary intake
- Use of DHEA supplements (long-term safety and efficacy data are still to be established)
With the cessation of ovulation, clinicians should remember that estrogen production may continue and be unopposed by progesterone. This exposure to unopposed estrogen for long periods of time can lead to endometrial hyperplasia, which is a precursor to endometrial cancer.24
Other clinical and systemic effects
Perimenopause and the MT affect the health status of other body systems beyond those of reproduction; notably these include bone health, cardiovascular health, cognitive health, and the important association of breast cancer with menstrual hormonal changes and therapies.
1. Bone health
It is estimated that of the 10 million Americans with osteoporosis, about eight million, or 80%, are women.25 Osteoporosis and osteopenia are preventable sequelae of estrogen depletion that occurs during perimenopause and the MT.4 Osteoporosis is characterized by a decrease in bone density that leads to abnormally porous bone, along with weakened skeleton, which often results in fractures. Osteopenia is when bone is slightly less dense than normal bone but is not as severe as osteoporosis.26 Women entering perimenopause have a rapid loss of bone mineral density (BMD) because bone resorption, uncoupled from bone formation, is accelerated while formation continues at the premenopausal rate. Trabecular bone is affected more than cortical bone; thus, bone loss is more commonly observed at vertebral, coaxial, and radial sites.27
The status of bone health has been linked to the age and bone mass when a woman enters perimenopause; the younger the woman is when ovarian function ceases, the more severe bone loss is likely to be and the lower the bone mass at menopause, the more severe the osteoporosis.15 Other risk factors for osteoporosis include race, being worse in white women than in Asian, with African-American women the least affected, as well as history of smoking and slender build.15
2. Cardiovascular health
Coronary artery disease (CAD) is the primary cause for morbidity and mortality in men and postmenopausal women in the US. In 2017, the CDC estimated 1 of every 4 American women died due to heart disease.28 Due to declining levels of estrogen in perimenopause, the risk for CAD increases in older women.16 Numerous studies have also shown that the prevalence rates for hypertension (HTN), thromboembolism (TE), dyslipidemia, weight gain and obesity, metabolic syndrome (METs) and type 2 diabetes (T2D) all increase and may be attributed to the estrogen deficit of perimenopause and into the MT.29-31
The beneficial effect of estrogen on reducing cardiovascular mortality is due to many factors. One mechanism appears to be estrogen’s effects on lipid metabolism, which includes lowering low-density lipoprotein (LDL) and increasing high-density lipoprotein (HDL). Studies have suggested that the best predictors of CAD in men and women are different between the genders and that triglycerides, HDL, and lipoprotein(a) may be more significant in women.32,33
3. Cognitive health
The number of peer-reviewed research findings assessing the association between estrogen and memory function has been growing in recent years, but further research is needed to elucidate the specific processes by which estrogen exerts direct effects on cognitive health. Normal aging itself induces a decline in certain cognitive capabilities, with complaints of forgetfulness and mental fog that may be a result of estrogen deficiency.
Findings from a recently published study suggested that the metabolic brain changes associated with menopause may increase the risk for Alzheimer’s disease (AD).34 In this small study, the researchers compared the positron-emission tomography (PET) scans of premenopausal, perimenopausal, and menopausal women and found that the perimenopausal and menopausal participants exhibited brain hypometabolism in the same brain regions as patients with clinical AD.34,35 These findings, according to the authors, suggest a “progressively increased risk of an AD endophenotype in women who undergo the perimenopause-to-menopause transition and suggest that endocrine aging outweighs the effects of chronological aging in the female’s brain several years, if not decades, before possible clinical symptoms emerge…the optimal window of opportunity for therapeutic intervention in women is early in the endocrine aging process.”34,35
Data have suggested that AD is more common in women than in men, even when the longer average lifespan of women is taken into account, because AD is primarily an age-related condition.36 The effect of estrogen slows the decline of preserved memory function, and studies have shown that exogenous estrogen, administered after a clinical diagnosis of AD, does not improve, or reverse, cognitive function in AD nor delay the onset of AD.37,38
Mood changes, including increased irritability, depression, and anxiety, are also common complaints during perimenopause and the MT. These have been attributed to direct effects of declining estrogen on serotonin and norepinephrine as well as being secondary to estrogen related VMS, night sweats, and sleep disturbances.39 Over 70% of women describe irritability as their main emotional problem in perimenopause, and depression has been found to affect 20% of women progressing through the MT.40,41
4. Breast cancer
Breast cancer is the most common female cancer worldwide. In the US, 1 in 8 women (about 12.4%) will develop breast cancer over the course of their lifetime.42 Breast cancer development involves both genetic factors as well as lifetime exposure to estrogen. Recognized genetic factors involve significant mutations in BRCA 1 and 2, CHEK2, TP53, LKB-1, and PTEN occurring in 5–10% of patients.43,44 Epidemiologic and experimental data implicate estradiol (E2) as another contributing factor. While exact molecular mechanisms of how E2 influences breast cancer development are not well understood, the most widely accepted theory, supported by extensive experimental evidence, suggests that E2, acting via estrogen alpha receptors (ERα), stimulates cell proliferation and initiates mutations that occur as a function of errors during DNA replication. The promotional effect of E2 subsequently supports growth of cells harboring mutations, which then accumulate until cancer ultimately results.45-47
Much controversy exists about the use of estrogen and breast cancer. Some studies show an increased risk of breast cancer with postmenopausal estrogen use; others show a decrease.23,24 A possible link to cancer is also suggested by the finding that breast cancer risk is increased in women with an earlier age at menarche and a later age at menopause.48 However, a reduction in risk is observed with early age at pregnancy and the interruption of menstrual hormonal changes.48 The role of estrogen in the development of breast cancer continues to be studied.
5. Sexual dysfunction
With greater access to healthcare, augmented life expectancy, and sharper focus on improving lifestyle and nutritional intake, women transitioning into menopause can expect to live for another 25 years.60 With the increased expectations for a longer and healthier life, women are also thinking more about quality of life issues, which include maintaining sexual function well into perimenopause and beyond. The Study of Women’s Health Across the Nation (SWAN) found that more than 75% of middle-aged women reported sex was moderately to extremely important to them and their quality of life.51
Sexual dysfunction subtypes include dysfunction linked to desire, arousal, orgasm, and sex pain disorders (vaginismus and dyspareunia).51 Menopausal women often seek medical advice because they experience one or more of these subtypes. A variety of nonprescription, prescription, and investigational products to treat female sexual dysfunction is available, but the evidence regarding the effects of these products on female sexual function (FSD) remains inconclusive.52
A review of the literature suggests prior to recommending pharmacologic treatment in women with sexual dysfunction, behavioral therapy should be undertaken as an important first step. This therapy may help women overcome psychological barriers toward sexual activity, modify sexual behavior, and subsequently improve sexual function, but it is not sufficient by itself to resolve FSD.52 This was underscored by newly published findings from a systematic review.53,54 In that study, researchers assessed 103 studies with 42 different treatment modalities (including 26 different classes of drugs). The most common therapies included hormonal therapy (25 studies), phosphodiesterase type-5 inhibitors (9 studies), botulinum toxin A (5 studies), and flibanserin (5 studies). The psychotherapeutic approach was detailed in 36 articles, while 3 studies utilized homeopathic treatments.53 The authors concluded that due to the wide variability of treatment and outcome measures across the literature and the complexity of FSD (despite marked improvement in specific FSD domains), neither psychotherapeutic interventions nor pharmacologic options alone demonstrate consistent disease resolution and perhaps require a combination of the two in with individualized care, as each woman has specific needs that will require personalized treatments.
Drug options for FSD still require comprehensive, long-term studies with bigger sample sizes and validated outcomes measures but include the following:52,55,67
- Estrogens: To improve vasomotor symptoms, vaginal dryness, dyspareunia, and general wellbeing but has little effect, in most women, on libido
- Testosterone: Replacement of this hormone enhances sexual motivation and does improve libido
- Tibolone: Has estrogenic, progestagenic, and androgenic properties and has been shown to positively affect some types of FSD
- Dehydroepiandrosterone (DHEA): Recent studies have shown the beneficial effects of intravaginal DHEA on moderate to severe dyspareunia or pain at sexual activity often due to vulvovaginal dystrophy
Sexual functioning is an imperative component of women’s lives, and women’s sexuality is highly capricious and multifaceted, embracing a composite chemistry of physiologic, psychological, and interpersonal aspects; complaints and adverse issues regarding FSD should be addressed individually for optimal outcomes.
Epidemiology & health economics
An estimated 6,000 women reach the perimenopausal transition every day in the US, and more than 6 million American women report experiencing a myriad of adverse symptoms including hot flashes (vasomotor symptoms [VMS]), night sweats, insomnia, vaginal dryness, mood disorders such as depression and anxiety, and sleep disturbances.56,57 A decrease in urinary pH may lead to changes in bacterial flora and could result in new or increased number of urinary tract infections, pruritis, and discharge.1 These unwanted symptoms and their negative effects can be seen with reduced mental and physical quality of life scores, poor personal relationships, decreased occupational productivity, and impaired daily activities.
Menopausal symptoms may result in increased economic burdens on women and society due to the direct costs of provider and emergency department (ED) visits, prescriptions and over-the-counter medications, labs, and management of therapy side effects.58 In a recent study, the total health expenditures in the US for menopausal symptoms were estimated at $3 billion annually,59 and in another analysis, the annual direct costs of VMS were estimated at $1,346 per person with annual indirect costs (primarily resulting from absenteeism) being estimated at $770 per person.60
Though each woman’s experiences of perimenopause and the MT are unique, and many women do not report any major complaints other than irregular menses that stop with menopause, most women experience several unwanted symptoms that can start as early as six years before the final menstrual period.2,3 As the menopausal and postmenopausal years progress, there is an ever increasing loss of ovarian response to gonadotropins, and the affective symptoms of the MT also decline over time.12
The complaint most often experienced, and reported, by over 75% of perimenopausal women is VMS.61-63 VMS can cause embarrassment and discomfort, and when these symptoms occur at night, they are called “night sweats” and may lead to significant sleep disturbances. VMS episodes can last one to five minutes and may be associated with perspiration, flushing, chills, anxiety, and even heart palpitations.64 Other complaints most widely described include:18
- Vaginal dryness and pruritis
- New or increased number of urinary tract infections
- Mood disorders (usually anxiety and/or depression)
- Weight changes
- Mastodynia/mastalgia (breast pain)
Common signs and symptoms
On pelvic examination, the clinician may observe more obvious signs of hormonal depletion. The reproductive organs of a woman prior to entering perimenopause are vastly different from those seen during the MT or perimenopause. Some common signs and symptoms are:12
- Thinning of vaginal epithelium, which contributes to vaginal dryness, dyspareunia, and pruritis
- Shrinking of uterus and ovaries (ovaries are usually nonpalpable in menopause)
- Reduced size and symptoms of fibroids
- Alleviation of symptoms of endometriosis
- Loss of pelvic muscle tone (sometimes manifested as prolapse)
Usually a diagnosis of perimenopause or the MT can be evident from a complete and carefully conducted history and physical examination. However, common causes for changes in the menstrual cycle must also be considered in patients who may not have clearly defined symptoms or may not entirely fall within the appropriate age range. Some etiologies for menstrual changes include:65
- Hyperthyroidism: irregular menses, sweating, and mood changes
- Pregnancy: amenorrhea (absence of menses), mastalgia, mood changes
- Hyperprolactinemia: amenorrhea, headache, vaginal dryness, mastalgia, and discharge
- Medication effects or interactions may lead to increased sweating and/or headache
As the signs and symptoms of perimenopause can last from 6 months to 10 years prior to the occurrence of menopause, it’s important to recognize and identify any alterations in physical health starting around age 40 that could signal subtle hormonal changes. Regularly scheduled wellness visits and follow-ups may help ensure optimizing perimenopausal outcomes.
The aim of a workup or assessment for perimenopause is to determine management options for acute symptoms (for example, VMS) or any complications (such as osteoporosis), to help avoid risk for potential complications (thromboembolism or fracture), and finally, to ensure appropriate treatment considerations are in place (Table 2).
Table 2. Suggested workup for patient in perimenopause/MT66
Management & treatment options
Perimenopause (or the MT) is a gradual transition, and clinicians may be able to evaluate where their patients are on this transition timeline with a good history, physical exam, labs, and tests; however, managing adverse and unwanted effects and complaints may require not only medications but discussions with the patient to encourage adding lifestyle modifications and behavioral changes to improve outcomes.
Conventional medicine has long touted the implementation of pharmaceutical therapies for symptoms of the perimenopausal stage, but more and more patients (and their physicians!) are also requesting natural options as well as implementing lifestyle changes to address other aspects of “the change.” It is recommended, however, that all natural therapies be taken under HCP supervision. Lifestyle modifications can—and should—be added to either drug or natural therapy options, but caution and monitoring by a healthcare provider (HCP) should be ensured before combining drug therapy with natural therapy to avoid any possible interactions or adverse events. A listing of the various management and treatment options, whether pharmaceutical, lifestyle, and/or natural are listed below67,68 (Table 3).
What we have found to be most impactful lifestyle medicine treatments for my patients are the following. I prescribe one or more of these treatments for six weeks, and in the meantime, I collect genomic and biomarker data if the patient is considering hormone therapy.
- Elimination diet for 21 days to 3 months. From the scientific literature, cutting out caffeine and gluten have been shown to improve estradiol, sleep, and inflammation.
- Paced respiration is a low-tech methodology that has been shown to reduce hot flashes by 44 percent.69Here’s how to coach your patients: Breathe deeply for 20 minutes twice per day with a 5-second inhale, a 10-second hold, and 5-second exhale.
- Chasteberry to help with declining progesterone and menstrual regularity.
- Siberian rhubarb to reduce hot flashes, night sweats, brain fog, and anxiety.
When symptoms do not improve or only partially improve after six weeks, I move next to a robust and updated risk, benefit, and alternative discussion about hormone therapy options, starting first with FDA-approved bioidentical transdermal estradiol combined with micronized progesterone.
Table 3. Summary of treatment options for the patient undergoing perimenopause/MT
With an aging population, an increasing number of women are experiencing the roller coaster known as the “change of life,” which translates as perimenopausal symptoms. While common complaints include more frequent menses, then skipped menses, vasomotor symptoms, vaginal dryness, and sleep disruption, many women are unaware of the effects perimenopause and the menopausal transition have on other body systems beyond reproduction, such as bone health, cardiovascular health, and cognitive health. Ultimately, estrogen is the master regulator in the female body. Without it, patients may feel, as one put it, “neutered.” Our task as practitioners of personalized lifestyle medicine is to help our patients navigate the sometimes wild ride of perimenopause and menopause, with expert and evidence-based guidance regarding the safest and most effective treatments for perimenopausal and menopausal symptoms.
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