Role of Hormones over the Lifespan: How Hormone Balance Affects General Health and Well-Being at All Ages

Abstract

Hormones define who we are. From puberty to late post-menopause, the changes in our sex hormones affect every other hormone in our body. This article will explore the state of the science and the clinical application of hormone therapies at various ages and during various periods of female lifespan. Literature review of hormone therapies, state of the science compared to clinical practice in areas of hormone therapies, the role of class effects, the public and medical training understanding of the role of hormone therapies, and the future possibilities for education and research in the areas related to hormone therapies. Clinical correlation and relationship between scientific data published in PubMed and Google Scholar and public and practitioner understanding of hormone therapies.

1. Introduction

As early as 1889, the Merck manual listed “Ovariin” an oral powder derived from dried cow’s ovaries, as a treatment for “climacteric, “the term used for menopause at the time. The use of hormone therapies for treatment of symptoms of menopause is not new to our generation, and research and scientific data abound in the past 30 years of PubMed, SCOPUS, or Google Scholar. However, if one went to medical school and post-graduate training in the past 50 years, one would think hormone therapies are recent developments and the research and confusion surrounding them started as recently as the year 2002 in the wake of the failure of the Women’s Health Initiative.

Although we are still mired in confusion surrounding gonadal hormones the data is available to try to put some clarity into the situation. The use of nomenclature, presence or absence of class effect, various roles hormones play, use and symptoms associated with hormone changes at various ages and the safety of their usage need clarification in order to achieve our goal of accomplishing a thorough understanding leading to appropriate use of hormones in prevention and enhanced lifespan.

The confusion is primarily due to semantics and politics affecting the practice of medicine. Medical education is lacking in the area of training on female hormones. The confusion must be eliminated as much as possible so providers can have effective and safe information and training to take care of patients and focus on improving the patient’s quality of life. There is dire need to provide education on the role of hormones in health and longevity, conduct more clinical and comparative studies and provide answers to questions that focus on the long term clinical application of the use of hormones and share the information we have on larger scale.

In this chapter, we will attempt to provide a scientifically sound, clinically based and research supported perspective on gonadal hormones, their roles in females at various phases and stages of their life based on the most up-to-date scientific data from Google Scholar, PubMed and Cochrane review.

2. Types of hormones and interactions

Modern science’s transformative impact in the area of gonadal hormones was heralded in 1922 with Allen and Doisy’s identification of the ovarian cycle and the discovery of estrogen. By 1936, pharmaceutical companies like Schering and Richter were already developing oral contraceptives (BC pills) and synthetic hormone replacement therapies (sHRT). Over the following 15 years pharmaceutical advances led to wider patient accessibility and increasing use of hormone-related interventions, such as BC pills for ovulation suppression, pregnancy prevention and conjugated equine estrogen (CEE) to alleviate menopausal symptoms (Premarin™). As synthetic (non-human identical) hormones were developed bio-identical hormones (molecularly identical to human hormones) were also manufactured. The process of manufacturing hormones is all synthetic regardless of what raw materials are used (plant based or laboratory developed). The molecular formulas vary. From the outset, as more HRT and contraceptive drugs were developed and came to the market, the distinction between their actions at the molecular level was lost. They were all regarded as one class of drugs. Although their actions may have varied, they became viewed as one, that is, estrogens and progestogens. This situation lead to the erroneous assumption that all estrogens and progestogens have the same effect.

The introduction of the BC pill (must be synthetic in order to suppress ovulation) and sHRT (sourced inexpensively for reasons of cost and availability) initially held promise. To this day BC pills work well to prevent ovulation and pregnancy and Premarin helps reduce vasomotor symptoms (VMS) of menopause. However, in time and as a consequence of numerous small studies undesirable side-effects appeared leading to a constant search for better pharmaceutical options and more research and development.

It’s important to note that the impact and interactions of hormones vary in women at all ages and phases of their life. The complex interplay of gonadal hormones and their intricate and crucial roles shape human development, metabolic processes, fertility and overall health.

3. Hormones in puberty and adolescence

The onset of puberty, marked by the increase production and release of gonadal hormones, triggers sexual expression leading to maturation and gender differentiation. This hormonal upsurge typically occurring between ages 9–16 in girls, manifests physically with the development of secondary sexual characteristics. Hormonal stimulation at puberty alters specific glandular activity leading to adult body odor, pubic and axillary hair. The onset of menstruation occurs as the maturation of the reproductive system and the cyclic release of estrogen and progesterone are established. Fluctuating hormone levels also affect psychological development. Hormone changes may lead to anxiety, identity issues, mood swings, insomnia, weight gain, brain fog, even depression during puberty. Increased sebum production induced by hormonal changes, coupled with skin cell buildup may lead to acne. The hormonal shifts during puberty represent the transition from childhood to adolescence to adulthood manifested in many physical and mental changes also including hair growth and distribution, mood swings and phenotypical changes [1].

The gonadal hormones; estrogen (E1, E2, and E3), progesterone, and testosterone, play a critical role in their interaction with other hormones like insulin, thyroid, and adrenal hormones. This indelible connection between all hormones becomes clearly noticeable and continues for the rest of the woman’s life although it’s often overlooked during clinical patient evaluation.

With the emergence of a rhythmic hormonal journey estradiol, progesterone, and testosterone lead to regular or irregular cycles, amenorrhea, or pregnancy. The master regulator of the actions and interactions between gonadal hormones and other hormones and metabolic processes is the HPA (hypothalamo-pituitary-adrenal axis). The final product is an adult woman with gonadal hormones taking their position in the cascade of all bodily functions through bi-directional messaging up and down the HPA.

The fluctuations of gonadal hormones determine fertility, libido, moods among other metabolic processes. As a female’s menstruation may become more regular in her twenties, a monthly cycle of preparing for pregnancy occurs, guided by the rise and fall of estradiol, progesterone, and testosterone.

4. Hormones in pregnancy

A complex interplay of hormones during pregnancy orchestrates massive physiologic changes to support fetal development. They include to our present knowledge human chorionic gonadotropin (b-hCG), estrogen (estradiol and estriol), progesterone, and prolactin. The placenta produces Beta-hCG and maintains the corpus luteum, which in turn continues producing progesterone to sustain and enhance the uterine lining. Estriol, the estrogen of pregnancy is produced by the placenta rising gradually, contributing to increasing uterine size, blood flow, and mammary gland development while prolactin prepares the breasts for lactation. The fine interplay between all these hormones lead to the growth of the fetus during the 40 weeks of gestation and the changes in the maternal body to accommodate the fetus and its growth.

In Vitro Fertilization (IVF), via hormonal manipulation, egg maturation and reproductive cycle control is induced with a combination of pharmaceutical and human identical hormones (bHRT). Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) (both pharmaceutically manufactured yet human identical (bioidentical) in their molecular structures are administered to induce ovulation, while progesterone maintains the uterine lining ready for implantation. IVF therapy offers significant benefits (the promise of pregnancy and delivery of a viable fetus to women who are having difficulty conceiving naturally), but also presents risks. Risks include multiple pregnancies, which may lead to preterm birth and low fetal weight, ovarian hyperstimulation syndrome, potentially causing serious health issues and/or early menopause. Ethical concerns about surplus embryos and the emotional toll of failed cycles significantly impact individuals and affect relationships of couples undergoing IVF. Lastly, some research raises possibilities of increased risk of hormone sensitive cancers such as ovarian and breast and premature ovarian failure in women who undergo multiple IVF cycles [2].

5. Post partum period

Postpartum, hormone levels undergo rapid changes. Estrogen and progesterone levels drop precipitously as the placenta is expelled, triggering prolactin release and milk production. Oxytocin stimulates uterine contractions to shrink the uterus to pre pregnancy size, create the emotional bond between the mother and baby and commence the milk letdown reflex. Additionally, cortisol and thyroid hormones collaborate with gonadal hormones impacting energy levels, sleep, mood and metabolism. It takes time for hormones to return to pre-pregnancy levels, and this transition varies among individual women. The hormonal shift may contribute to mood changes and may lead to from elation and total attachment to newborn to postpartum blues and depression. An infinite number of factors influence the postpartum experience for women—vaginal simple, complicated versus Caesarian delivery, complications during gestation or birth, social and psychological support systems and often unaddressed yet highly important environmental factors.

Problems that can arise during the postpartum period include postpartum hemorrhage, infection, perineal pain or tears, breastfeeding difficulties, vaginal dryness and loss of libido. There is a glaring absence of research and provider training during this critical period or a woman’s life. Once the baby is delivered and is healthy, the woman has very few medical resources to provide educational and emotional support during this life altering transition. It is crucial to address and create individualized postpartum care plans to appropriately provide help for the diverse needs of the individual woman. There is little data or research at this point in this area but the need is dire and it’s no longer acceptable to discharge a woman by ob-gyn with 6 week follow up and be told she can have sex.

6. Hormones in thirties and forties; pre and perimenopause

During the late thirties and forties, hormone levels may start to change leading to irregular menses, ineffective and infrequent ovulation. While menstrual cycles continue, the hormone levels are not the same as in the 20s and 30s and the impact on the female body starts to reflect these changes. Waiting until menopause to address hormone balance misses an entire decade of life. Being mindful of these changes and addressing them correctly makes a big difference in long term outcome.

The pre and perimenopausal periods can start as early as 30s and 40s. Although fertility may still continue to varying degrees, changes in frequency of menstrual cycles, brain fog, anxiety, vaginal dryness, weight gain, insomnia, thinning hair and decreased libido are signs of the change in hormones long before the onset of menopause. As a woman gets into her later 40s and early 50s menses become more irregular and symptoms like, hot flashes, night sweats, insomnia arise and directly affect the woman’s physical and emotional wellbeing. These may occur long before reaching the formal definition of menopause which is 1 year without a menstrual cycle yet symptomatically may be decades of discomfort and downward spiral in general health. Estradiol, progesterone, testosterone, thyroid and adrenal supplementation administered correctly in the right preparations treating the women’s symptoms with the support of biomarkers like bloods, body composition and physical examination may increase quality of life and even help women feel well enough to lead their lives unaffected by the symptoms of hormone imbalance which herald the onset of diseases of aging.

7. Hormones in menopause

The conventional medical definition is the cessation of menstruation for 12 months or more. Most commonly this occurs in the late 40s, early 50s. However, since as described above it is the hormone imbalance and the symptoms that occur that truly define the moment in time when women need help in terms of HRT the providers need a clearer understanding of what happens physiologically to the female body in this time period and be alert to these changes and treat accordingly.

7.1 Menopause symptoms

As hormones change during the decade prior to menopause a variety of physiologic and clinically significant changes start to unfold. Fluctuating mood likely due to the complex interactions between hormones, the HPA axis, insulin, cortisol and neurotransmitters may affect these shifts. Night sweats and hot flashes, triggered by thermoregulatory changes within the central nervous system, underscore the hypothalamic involvement in temperature control and symptomatic outcomes leading to poor sleep and metabolic instability.

Rapid spikes and troughs in hormone levels manifest as insomnia, disrupted sleep-awake cycles, possibly mediated by neuroendocrine mechanisms leading to poor quality of sleep and the side-effects thereof. Weight gain may also occur due to rapid shifts in estrogen and progesterone and HPA axis interactions leading to metabolic alterations, insulin resistance, metabolic syndrome and changes in appetite and dysregulated ghrelin and leptin release. Increased frequency of urination may also be directly connected to hormone changes.

Cessation of menses, the “hallmark definition of menopause,” reflects decreasing hormone production along with age and environmental factors. Painful intercourse, loss of libido often associated with vaginal dryness and atrophy also result from untreated hormonal depletion. Decrease in bone density follows decrease in estrogen levels emphasizing the importance of hormonal influence on skeletal health.

Within 10 years after menopause the risk of CV disease increases dramatically and rapidly becomes higher than in men [3, 4]. Women who are not treated with hormone therapies represent the higher end of risk for CV disease with age. At the same time, diabetes, metabolic syndrome, arthritis, hypertension and other diseases of aging start to appear.

In essence, menopause depicts myriad physiologic responses and symptomatic expressions, each intimately tied to hormonal fluctuations their eventual disappearance and its effect on all body systems. Age is the primary cause of increase risk and onset of disease but it is the lack of hormones that indelibly and invariably connects age to disease.

7.2 Menopause treatments

Sadly, menopause represents the worst season of a woman’s life but does not have to be. Physically and mentally most women who do not have access to proper HRT suffer ever increasing problems leading to chronic disease of aging [5].

The abrupt halt and the medical and media frenzy that followed the Women’s Health Initiative (WHI) study in 2002 essentially eliminated the HRT option for menopausal women and left in its wake millions of women suffering. The only conventional options offered at the time were antidepressants and wearing layered clothing and staying in dark cool rooms. Faced with such limited possibilities, many women turned to bioidentical-human-identical hormone therapies (bHRT) considered novel and alternative due to their intense marketing. The truth is they were pharmaceutically manufactured to mimic the exact molecular structure of estradiol and progesterone and were not novel nor alternative.

Starting in the mid 1950s to the early 2000 the most common form of hormone therapy for menopause was conjugated equine estrogen (CEE) and BC pills (initially more popular in Europe).

In 2022 Fact or Fiction: The Role of Regulated Body-Identical Hormone Therapy for Menopausal Women, more than 40 clinical studies that demonstrated a 30–50% reduction in cardiovascular disease (CV) and all-cause mortality among women using HRT [6]. These findings and others led to a resurgence in use of HRT even though no new large scale studies have been undertaken since the early 2000s and there have been very few studies comparing actions of various types of gonadal hormones.

]The WHI was started in the early 1990s and although a large (double blind placebo controlled) DBPC governmentally sponsored study, did not compare sHRT to bHRT and looked at a population of women more than 10 years after menopause with other pre-existing conditions [7].

The WHI study was stopped abruptly after 5.8 years in 2002 due to unacceptable side effects. Although the data proved erroneous upon deeper review, doctors, medical societies and women stopped using HRT abruptly and suffered terrible consequences. These consequences were return of symptoms: hot flashes, night sweats, insomnia, weight gain, irritability, loss of libido, as well as depression, decreased cognitive function and loss of ability to perform at work and at home at premenopausal levels.

Given that the data of the WHI study was limited to sHRT an ever increasing number of women turned to bHRT for a safer alternative to manage their symptoms. bHRT is usually manufactured from plant extracts such as soy and yams oils and have the same molecular structure as human sex hormones. They are pharmaceutically produced and thus synthetic. Only their molecular formula is identical to the molecular formula of human hormones.

Both regulated (US FDA-approved) and compounded (not FDA approved, but using the same raw materials) bHRT therapies are widely available in the United States. Aversion to compounded bHRT is partly due to concerns that these products lack standards and evidence of purity, have not been rigorously tested, and may not be safe for women. However, to date there is no scientific evidence to support the claims of lack of safety. The most recent article on lack of reliability of bHRT comes from 2004 [8].

In contrast, FDA approved bHRT products such as 17-beta-estradiol and micronized progesterone are standardized and the active hormones are the same as the compounded ones. Since the WHI study, researchers and principle investigators have re-evaluated the results of the study reaching the conclusion it was flawed and did not truly reflect the situation in most women. In 2013, the final data was published in the BMJ by the principle investigators of the WHI study finding that all cause mortality in women on sHRT used in the study was lower than that of women on placebo [9].

Since the early 1990s many studies, some large scale have been conducted on the benefits and risks of HRT. In many of the studies, although never clearly stated there were arms that used bHRT which consistently seemed to produce better effects. These studies included the Danish Study, PEPI, and KEEPS trials. The arms of these studies that used bHRT with 17-beta-estradiol and micronized progesterone safely and effectively managed menopausal symptoms while minimizing endometrial hypertrophy, lowering risk of VTE and CV disease (improved HDL, decreased LDL) and improving insulin sensitivity [6]. Very few conventional studies on compounded hormones exist to date and most of them are limited and with low traction.

8. Class effect

The controversy between various formulations of HRT boils down to a lack of understanding of the concept of “class effect”. By class effect we refer to similar outcomes, both therapeutic and adverse from various medications categorized together as “one class” for whatever reasons chosen by pharmacologists or other scientific group [10].

In the 1930s when pharma developed hormones in the form of BC pills and CEE they were all assigned to the umbrella class of estrogen and progestogen. The assumption was made that all these variety of molecules they acted the same in the woman’s body. As more drugs came to market and studies were conducted, the concept of class effect swallowed up all gonadal hormones. In time, less differentiation between the effects of various hormones was made. Results of the studies that found risks like increased blood clotting, increased incidence of cancer, risk of dementia, etc. did not make any distinction between the hormone molecules involved in the studies.

When the WHI found increased risk of CV events all HRT were blamed. Apart from the fact that the study was poorly designed and the results proved incorrect, the issue of “class effect” was never addressed adding to the confusion. It was determined that all estrogens and progestogens used in menopausal women carried unacceptable risk and hence their usage was discontinued although they were not removed from the market. Their labels on the FDA approved products had to carry a black box warning albeit the WHI only studied CEE and medroxy-progesterone acetate. The human identical molecular formula estrogen- 17- beta estradiol and progesterone were lumped into this class effect melee and carried the stigma of the failed study albeit no study proven they had any negative effects. Sadly, this served to hurt millions of women since data on all studies that included the human identical formulations of estradiol and progesterone consistently demonstrated significantly lower risk profile for these drugs [7].

In 2011 at the International Menopause Society annual meeting in Rome, Italy, the issue of “class effect” came up for the first time in a global forum and scientists and researchers from around the globe agreed that neither estrogen nor progesterone were subject to class effect. The studies and clinical data proved that beyond a reasonable doubt there was no class effect in the area of HRT [11].

However, this significant information was not accepted or addressed in the US and still is not in medical training. The result has been more confusion, less education and initially, after the WHI study fiasco, the marketing of the compounded form of bHRT touted to be something new and different. That is not correct. bHRT has been around since the 1890s and the FDA approval of bHRT preparations that followed the WHI study only serves to confirm the low risk associated with bHRT.

The black box warning on FDA approved estrogens and progestogens serve to further confuse and separate from compounded bHRT.

As we continue to untangle the issue of bHRT vs. sHRT, once we understand and are no longer burdened by the class effect dilemma it becomes easier to address the use of hormone preparations at all ages and in various situations for various conditions. It is also easier to separate compounded vs. FDA approved HRT and focus on what works best for the individual patient.

9. Formulation, dosing routes, administration and safety of hormone usage

The FDA has approved all HRT for four specific uses:

1. Alleviating moderate to severe VMS

2. Safeguarding against postmenopausal osteoporosis

3. Addressing hypoestrogenism due to hypogonadism, bilateral oophorectomy, or premature ovarian insufficiency

4. Managing moderate to severe vulvovaginal symptoms.

In instances where FDA indications for systemic estrogen therapy are absent, FDA guidance recommends employing low-dose topical vaginal estrogen therapy as a solution for treating genitourinary symptoms linked to menopause.

Various synthetic estrogen formulations are available: CEE, conjugated estrogens, ethinyl estradiol. Conjugated equine estrogens, notably used in the WHI, are derived from pregnant horse urine including more than 300 estrogen like estrone sulfate, equilin sulfate, and estradiol sulfate. In postmenopaual women, estrone sulfate acts as an estrogen precursor converted into estrone (E3) and estradiol (E3) 17β-estradiol is molecularly identical to human estradiol.

Birth control pills contain many variations of sHRT because the goal is to suppress ovulation and with bHRT that cannot happen. Ethinyl estradiol, a synthetic estrogen, is primarily partnered with a progestin in hormone contraceptives.

When exogenous estrogen is used in women with a uterus, progestogens (including synthetic progestins as well as micronized progesterone) are given together continuously or in cyclical fashion. Progestogens include MPA, norethindrone acetate (NETA), norethisterone and micronized progesterone. While medroxyprogesterone acetate, levonorgestrel, and NETA are synthetic progestins, micronized progesterone is molecularly identical to progesterone produced by the corpus luteum. The rationale for progestogen usage originates from a 1975 article connecting use of unopposed synthetic estrogen to increased incidence of endometrial hyperplasia and potential risk of endometrial cancer [12].

Different progestogen types and dosages, administration routes, and regimen protocols (sequential or continuous-combined) may have distinct implications for health outcomes. Patient preference, a vital factor, must be taken into account, given that some women prefer regimens that avoid periodic menstrual bleeding.

A primary adverse outcome linked to synthetic progestins is the risk of breast cancer. Synthetic variants have the potential to stimulate and escalate the division of estrogen-related breast cells, essentially promoting the proliferation and spread of tumor cells. This unregulated cell division is considered as the genesis of cancer. Moreover, sHRT has been observed to metabolize estrogens in the body into more aggressive forms (such as 16-hydroxyestrone). These may be potentially harmful iterations of estrogen triggering the formation of cancer.

In contrast, bioidentical progesterone has demonstrated an opposing effect compared to its synthetic counterparts. Hormones that are bioidentical, like progesterone, obstruct the division of breast cells and have been associated with inhibiting breast cancer development (by interacting with kinase inhibitors). Naturally sourced progesterone has been described as having a safeguarding function within the female body by impeding the formation of breast cancer, whereas synthetic progestogens may actually encourage the onset of breast cancer. Bioidentical hormones may offer a safer, long-term alternative to the contentious synthetic alternatives [13].

10. FDA approved synthetic estrogen replacement therapy

ORAL

CEE

Conjugated Estrogen

Esterified Estrogens (Amnestrogen, Estratab, Evex, Femogen, Menest)

Estradiol Acetate (Femtrace)

Conjugated Estrogens (Cenestin, Enjuvia)

PATCHES

Alora, Climara, Esclim, Estraderm, Fempatch, Menostar

Emulsions

Estradiol hemihydrate (Estrasorb)

GELS

CEE (Premarin) –

Estradiol Acetate (Femring)

INTRAMUSCULAR INJECTION

CEE

Estradiol Cypionate (Depo-Estradiol, Estradiol Cypionate)

Estradiol Valerate (Delestrogen, Estradiol Valerate)

11. FDA approved estrogen human identical (bioidentical)

Estradiol - Minivelle, Vivelle, Vivelle-Dot)

GELS

Estradiol (Divigel, Elestrin, Estrogel)

SPRAYS

Estradiol (Evamist)

Estradiol (Vagifem)

CREAMS

Estradiol (Estrace)

Estradiol (Imvexxy)

RINGS

Estradiol (Estring)

Polyestradiol Phosphate (Estradurin) previously available in the U.S. but was discontinued

12. FDA approved synthetic estrogen and progestogen combinations

Conjugated Estrogens and Medroxyprogesterone Acetate (Premphase (Premarin, Cycrin 14/14)

Premphase 14/14, Prempro, Prempro (Premarin, Cycrin), Prempro/Premphase) Estradiol and Drospirenone (Angeliq)

Estradiol and Norethisterone Acetate (Activella, Amabelz)

Ethinylestradiol and Norethisterone Acetate (FemHRT)

Estradiol and Levonorgestrel patch (Climara Pro)

Estradiol and Norethisterone Acetate (Combipatch)

Medroxyprogesterone acetate (Provera)

Norethindrone

Hydroxyprogesterone

Levonorgestrel (Mirena, Skyla, Kyleena)

Drospirenone (Slynd)

13. FDA approved progesterone human identical (bioidentical)

Micronized progesterone capsules or creams

Prometrium (oral micronized progesterone)

Utrogestan

14. Diseases of aging and the role of hormones

Hormones serve as signaling molecules that orchestrate physiologic responses, and their decline and eventual disappearance during the aging process brings closer the onset and progression of age-related diseases.

The aging process is characterized by alterations in endocrine function, resulting in permanent hormone decrease and disappearance. Such changes impact metabolic pathways, immune responses, inflammatory changes and tissue integrity, leading to lowered defenses against diseases, the hallmark of age. Reduction in estrogen, progesterone and testosterone contribute to bone loss and increased vulnerability to osteopenia and osteoporosis.

Age-related changes in hormone signaling pathways appear as chronic conditions such as cardiovascular disease, diabetes, cognitive dissonance and neurodegenerative disorders. Insulin resistance, a hallmark of type 2 diabetes, is linked to impaired insulin signaling and function, which may arise in conjunction with alterations in hormone receptor interactions and downstream signaling cascades [14, 15]. Dysregulated hormone levels, such as cortisol in response to chronic stress, play a role in immune system dysfunction and inflammatory responses, fostering an environment conducive to age-related diseases.

The intricate interplay between hormones and aging involves biochemical interactions that impact many physiologic processes. Understanding these relationships is crucial for elucidating and even preventing the mechanisms of age-related diseases and developing targeted interventions to mitigate their impact on age while using hormones in prevention.

15. NAMS and future research

The 2022 North American Menopause Society (NAMS) -Hormone Therapy Position Statement summarizes the most recent recommendations for hormone therapy. It emphasizes the balance of risks and benefits, along with guidance for managing menopause symptoms. NAMS position states that hormone therapy is most effective for addressing VMS, genitourinary syndrome, bone loss, and fractures. The statement underscores the importance of individualized care and shared decision-making in treatment. Patients should be regularly assessed for risk-to-benefit ratios, with appropriate doses, duration, and administration routes tailored to manage symptoms and treatment goals. No definitive time limits or type of hormone therapies are recommended.

The most recent Position Statement offers specific recommendations for clinicians, including the impact of hormone therapy on type 2 diabetes, considerations for longer-duration therapy, and the safe use of low-dose vaginal estrogen therapy for select cancer survivors. It also addresses non-estrogen alternatives for dyspareunia, the influence of age and time since menopause on risk stratification, and the nuanced breast cancer risk associated with different hormone therapies.

Evaluating benefits and risks is crucial, with NAMS highlighting that for most healthy symptomatic women under 60 within 10 years of onset of menopause, “the benefits of hormone therapy outweigh the risks and should be the first line of treatment”. The Position Statement extends to female patients with ovarian insufficiency and early menopause, suggesting hormone therapy until the mean age of menopause if appropriate.

In essence, the 2022 NAMS Hormone Therapy Position Statement serves as a dynamic tool guiding both clinicians and patients through informed decision-making and individualized care. While based on current evidence, treatment approaches must consider individualized risk-to-benefit ratios to ensure the best possible care [16].

16. Summary

At all life stage, hormones orchestrate intricate processes, influencing reproduction, metabolic functions, and overall health. Always remembering the omnipresence and ubiquitous role of hormones is crucial for maintaining well-being during every phase of life. While diet, exercise, sleep, stress management, supplements and conventional medical care have integral roles in maintaining health, the lack of hormones balance make prevention and delay of diseases of aging impossible to achieve. Hormone replacement therapy is the torchbearer, managing symptoms and signaling the dawn of a new phase, where hormones and time build a story of evolution--of the female spirit’s indomitable journey. For a healthier and more optimal life, it is crucial to have access to honest, research driven and informative education about hormones.