MENOPAUSE AND HORMONE REPLACEMENT THERAPY: DO THE BENEFITS OUTWEIGH THE RISKS? (PART 1)

Hormone Replacement Therapy (HRT) is commonly prescribed to women with pressing menopausal symptoms, as well as to help protect against age-related diseases such as osteoporosis. Since the early 2000s, HRT has been met with skepticism due to its associations with breast cancer and other complications. Recent research has called for a re-evaluation of these claims, highlighting that HRT can be safe, effective, and even complement healthy female aging.

The following article attempts to summarize what is currently known about HRT in the context of hormonal decline, menopause, and female aging:

• Part 1 below discusses the causes of menopause, symptoms, the benefits of HRT and how it works, as well as synthetic forms of HRT.
• Part 2 discusses natural forms of HRT, oral vs. transdermal administration, side effects, contraindications and the risks involved, as well as other treatment options for menopausal symptoms. Healthy diet and lifestyle considerations for optimal female aging are also briefly reviewed.

What Causes Menopause?

The first word that ought to come to mind here is ‘hormones.’

From the time we are conceived, the hormones inside of us work to propel our cellular chemistry and coordinate multiple processes, most of which pertain to growth, immunity and metabolism. As we age, our hormones fluctuate and eventually decline, giving rise to different stages of our physical development.

The Importance of Female Sex Hormones. In females, the main sex hormones that ensure reproductive health and the development of secondary sex characteristics are estrogen and progesterone. Aside from servicing the reproductive organs, estrogen and progesterone are essential for the functioning of many bodily tissues, including the bones, the brain and the immune system. The reproductive hormones are mostly produced in the ovaries, with small amounts being produced locally in peripheral tissues. There are four main types of estrogen, yet estriol (E3) and estretrol (E4) are only produced during pregnancy. The other two are estradiol (E2) and estrone (E1), which are known to be the main hormones involved in facilitating optimal female hormonal health.^[1]

Ovarian Decline and Menopause. Women have a finite supply of follicles that house hormone-producing egg cells. Throughout each menstrual cycle, a follicle becomes disrupted, and this process gives rise to the natural production of estrogen and progesterone that services the reproductive cycle as well as many other tissues in the woman’s body. Eventually, the number of viable follicles reaches its limit, causing cycle disruption, a rapid hormonal decline, the onset of menopausal symptoms, and eventually, the complete cessation of ovarian hormone production. ^{[2] [3]}

Low Estrogen and Menopausal Symptoms. Estradiol (E2) is the main hormone that declines in menopausal women. This hormone can be considered the “master estrogen” as it has the most potent binding affinity for all estrogen receptors. When E2 declines, estrone (E1) starts to take precedence in menopausal women. However, the levels of E1 are still far lower than in pre-menopausal women. Symptoms may arise during the adjustment phase if the rate of hormonal decline is too rapid.

Postmenopausal Hormones. After menopause, small amounts of hormones are still produced by the ovaries, adrenal glands, and other bodily tissues. The main hormones in circulation are androstenedione (a form of testosterone)^[4] and estrone (E1). Forms of testosterone can be converted in peripheral tissues into estrone, estradiol, and progesterone, helping to regulate the whole-body effects of ovarian decline.^[5] For the remainder of the female lifespan, these remaining sex hormones then see a gradual decline and are known to further influence the aging process.

Sex Hormone Receptor Expression. Estrogen and progesterone need to bind to their respective receptors to exert actions on the cell. The expression of receptors as well as their ratios with respect to one another, tend to dictate the actions of hormones in the body.

• Estrogen Receptors. The best-studied estrogen receptors include estrogen alpha (ER-a), beta (ER-b), and GPER (G-coupled Protein Estrogen Receptor). ER-a and ER-b are located inside the cell and inhibit the actions of one another, thereby regulating one another’s activity. It is undecided whether ER-a or ER-b activation would provide more benefit in non-reproductive tissues. However,  some reviews suggest that ER-b activation would be more beneficial for rectifying menopausal and age-related symptoms. It has been shown that estrogen receptors can still exert their vital cellular actions in the absence of hormonal activation. However, the degree of their activity is more or less halved. Growth factors and exogenous estrogens from dietary sources are also capable of binding to estrogen receptors and promoting similar effects to estrogen itself.
• Progesterone Receptors. Progesterone tends to balance the actions of estrogen in the female body and is known to have three main receptors: Progesterone receptor A (PRA), PRB, and PRC. As seen with ER-a and b, PRA and PRB regulate one another through inhibition.^[6] Far less is known about the function of progesterone and its receptors in cells, yet most evidence indicates that progesterone is as important as estrogen in the female body.

Menopause Symptoms

The process of hormonal decline in women has been divided into three phases: perimenopause, menopause, and post-menopause.

Since all the sex hormones are used by every cell in the body, the symptoms of menopause can vary between women. Common symptoms pertaining to each phase of menopause are touched on below.

Perimenopause can be considered the start of menopause and may kick in anywhere from 2-10 years before actual menopausal symptoms manifest. For most women, this is usually between the age of 45 and 50.^[7] In this phase, the ovarian hormone supply is only just beginning to drop. Thus, symptoms are less severe and tend to worsen until total hormone deficiency has occurred.

In some rare cases, perimenopause can begin as early as 30. Such early onset is typically the result of pre-existing medical conditions (endometriosis), certain treatments (e.g., hysterectomy or chemotherapy), or genetic abnormalities.

Perimenopause Symptoms include:

• Irregular menstrual cycles (2-11 months apart)
• Mood swings
• Heightened stress levels
• Poor sleep quality
• Fatigue
• Occasional hot flashes
• Decline in libido

Menopause is characterized by the absence of menstruation (for at least 12 months) and near-complete hormone deficiency. Women tend to hit menopause at some point in their 50s.^[8]

Symptoms of Menopause include:

• No menstruation (12 months or longer)
• Any symptoms of perimenopause
• Moderate to major weight gain
• Decrease in bone mineral density
• Depression (in some women)
• Regular hot flashes and night sweats
• Insomnia or interrupted sleep
• Constriction of arteries (may contribute to cardiovascular problems, hypertension and other issues)
• Vaginal discomfort (dryness, painful sex, hot flashes, increased sensitivity)
• Headaches
• Lower concentration span

Postmenopause is the stage after menopause in which the body has finally adjusted to age-related ovarian decline. It is indicated by a complete absence of menstruation^[9] as well as many of the above-listed symptoms. Postmenopausal symptoms are closely linked with the aging process and can include:

• Confusion
• Mental fatigue
• Stress incontinence (loss of bladder control due to stress)

Some symptoms of menopause often disappear during postmenopause. For most women, hot flashes tend to dissipate within 7.4 years from menopause onset.

Diagnosing the Menopause

Generally, healthcare practitioners can detect the onset of menopause without needing blood tests to verify the case. It is standard practice for doctors to include the following parameters in women's yearly checkups from the time they are 40 or so as a way to screen for menopausal symptoms.

• Blood pressure – elevated blood pressure signals arterial constriction
• Weight – sudden weight gain is a common sign of menopause
• Height – loss of bone density often accompanies curvature of the spine, which can result in a decrease in height
• Breast palpation – breasts tend to decrease in size alongside ovarian hormones
• Vaginal examinations and pap smears - detects dryness, atrophy and abnormal uterine bleeding

Differential Diagnosis. Symptoms of many other health conditions overlap with menopause. If menopausal symptoms manifest before the age of 45, then it is important for a healthcare professional to rule out the following first:

• Scarring leading to menstrual obstruction. This can be the result of surgery, infections or anatomic defects, as seen in Asherman’s Syndrome.
• Endocrine disorders, such as thyroid dysfunction, adrenal insufficiency, PCOS, etc.
• Hypothalamic-Pituitary-Ovarian Axis dysfunction. This is a malfunction of the neuro-feedback loop between these organs and can be exacerbated by obesity, cancer, anorexia, premature ovarian failure, and many other medical conditions.

Does Hormone Replacement Therapy Work for Menopause?

Hormone replacement therapy (HRT) has been considered the gold standard for treating menopausal symptoms for several decades. All forms of HRT revolve around supplying the patient with adequate estrogen and progesterone to balance age-associated deficits.^[10]

HRT does not prevent aging but can help to alleviate menopausal symptoms of hormonal decline and improve the quality of a woman’s life while aging.

Why Opt for Hormone Replacement?

Menopause is not a linear process that looks identical for all women. The same can be said of every woman’s hormonal profile throughout the entirety of her life. Any slight deviation in the mechanisms that govern hormone production can result in a different hormonal profile, which will later translate into varying manifestations of menopausal symptoms.

Hormones have an extremely large range of action that is not limited to the reproductive system and that involves each and every cell in the body. Common problems associated with both menopause and female aging include aches and pains, lower mood and cognition, bone mineral deficits, lower libido and an increased risk for acquiring age-related diseases.

Hormone Replacement Therapy (HRT) can help to reduce the severity of menopausal symptoms as well as help to prolong age-related decline in overall health and well-being.

How It Works

In principle, HRT is known to work through remedying the deficit of estrogen and progesterone caused by ovarian decline at menopause.

HRT Increases Estrogen Levels and Provides Relief. The main estrogen supplemented in HRT is estradiol, which serves to increase the concentration of both E1 and E2. However, in healthy menopausal and postmenopausal women, supplemented E2 is mostly converted into E1, resulting in a mild increase in E2 levels. It has been proven that an increase in these two types of estrogen can slow aging and lessen the severity of menopausal symptoms.

Raised Estrogen Promotes Balanced Receptor Activation. E1 has a weaker affinity for estrogen receptors than E2 and preferentially binds to ER-a over ER-b. However, at higher levels, as seen in women undergoing HRT, E1’s main metabolite (2-OH-E1) has been shown to have a stronger affinity for ER-b^[11]. Hence, in healthy menopausal women, in whom hormonal conversion is optimal, HRT can help to ensure a smooth transition through menopause and enhance female aging.

Progesterone Balances the Effect of Estrogen Supplementation. Progesterone is recommended for women who have not had a hysterectomy, as it serves to balance the growth effects of estrogen. Postmenopausal women produce a fraction of the progesterone than pre-menopausal women, the bulk of which occurs during the menstrual cycle. While the effects of progesterone in the reproductive tract are well-known, its effects in the non-reproductive tissues are only just beginning to be explored.^{[12] [13]} Studies suggest that progesterone supplementation for 10-12 days of the month during HRT helps to support the anti-aging benefits of estrogen supplementation.

HRT Postmenopause. Studies indicate that HRT can be effective for managing menopausal symptoms even after menopause. However, the lower hormonal conversions from testosterone to estrogen and a gradual increase in free testosterone in elderly women ought to be considered.^[14] Testosterone exerts anti-estrogenic effects, yet may present other benefits during old age. As a result, the risks associated with HRT are greatly increased in women over the age of 60.

HRT Benefits Outweigh Risks for Most Women. Skepticism has arisen over the years due to the complexity of hormonal biology and the risks pertaining to female hormone supplements, such as breast cancer. Over the last couple of decades, research has indicated that the risks associated with HRT are minimal in the majority of healthy women. This is especially true of less synthetic forms and low-dose, transdermal products. HRT can increase pre-existing risks in some women pertaining to underlying hormonal imbalances, endocrine conditions and unhealthy lifestyle habits. The benefits and the risks of HRT are discussed in more detail throughout the course of this article.

10 Benefits of Hormone Replacement Therapy for Menopause

Over and above reducing the severity of menopausal symptoms, HRT can serve to protect against rapid aging and improve various aspects of health in older women. Some of the anti-aging benefits of HRT are discussed below.

1. Offers Menopause Symptom Relief. The greatest effects associated with HRT are the reduction of menopausal symptoms. HRT users often experience a great reduction in the frequency and severity of menopausal symptoms, including hot flashes, night sweats, vaginal dryness, itchiness or pain, and symptom-related sleep disruption. Symptoms may be improved by as much as 75-90%.^[15] Symptoms can return after cessation of treatment in approximately 50% of women. However, non-synthetic forms at low doses are generally well-tolerated until up to 10 years from menopause onset.
2. Helps Regulate Fat Mass. Estrogen and white fat are intrinsically linked, with estrogen being able to promote the growth of fatty tissue and fatty tissue being known to secrete estrogens. Due to this relationship, females typically carry more fat than males, with even (subcutaneous) fat distribution being associated with better health outcomes for women. Uneven (visceral) fat distribution is linked with hormonal imbalances, menopause and female aging. HRT has been shown to reduce visceral fat in menopausal women and promote a more balanced weight distribution and cardiometabolic profile.^[16]
3. Lower Risk of Metabolic Diseases. In line with the above point, HRT has been shown to increase HDL cholesterol and lower LDL cholesterol, as well as promote balanced insulin levels in women aged 45-64.^[17] The greatest benefits correlated with equine estrogens either alone or combined with cyclic micronized progesterone. HRT may also help to lower the risk of developing type 2 diabetes post-menopause by as much as 35%.
4. Reduced Atherosclerosis Risk. In postmenopausal women undergoing HRT, those with higher estradiol and lower testosterone levels were shown to have a reduced risk of developing atherosclerosis and other cardiovascular conditions.^[18] The effects were neutral with respect to women who maintained higher free testosterone levels, suggesting that supporting optimal hormone metabolism is important for optimal HRT results.
5. Anti-Aging Skin Effects. Estrogen decline is linked with changes to aging female skin, including reduced wound healing capacity^[19]. HRT enhances collagen maintenance, skin and nail texture^[20], and wound healing, substantially improving the vitality of the skin. In a small sample of menopausal women, HRT helped to lower the appearance of wrinkles and skin rigidity.^[21]
6. Cognition. In a small experimental study, it was shown that progesterone and estradiol both independently improved aspects of cognition in 29 women aged 45-55. Progesterone was shown to activate brain areas associated with learning and memory, while estrogen was shown to stimulate those pertaining to verbal cognition^[22]. Other studies suggest that estrogen alone had a more pronounced cognition-enhancing effect than when taken together with synthetic progesterone.^[23]
7. Dementia Prevention. Several studies show that HRT may reduce the risk of developing dementia (specifically Alzheimer’s Disease) by as much as 30% in women who begin the treatment within 5 years from menopause until the age of 65. After this time, HRT does not appear to offer any protection against dementia. These effects did not extend to HRT making use of estrogen and synthetic progestogen, which were proven to increase the risk for dementia.^[24]
8. Bone Mineral Density. In 208 postmenopausal women, low-dose transdermal estrogen (14mcg) was shown to improve bone mineral density by up to 2.6% in the lumbar spinal region and 0.4% in the hip.^[25] These benefits may be enhanced by safe forms of progesterone, which is required for female bone development. Other studies highlight that while HRT helps to promote healthy bone mineral density in postmenopausal women, the benefits are minimal, and it is not able to prevent osteoporosis. Instead, HRT is able to enhance the efficacy of other treatments for osteoporosis and help to prolong the bone mineral density loss associated with aging. Some studies also observe a reduced incidence of bone fractures in women who opt for HRT before 60.
9. Longevity. The use of HRT in relation to longevity is supported by conflicting research. Large scale trials have suggested that in women undergoing HRT within 10 years of menopause onset, cardiovascular-related mortality risk is reduced. Some studies have shown that HRT has the ability to conserve telomerase, maintain the integrity of telomeres, and promote longevity in menopausal women who make use of the therapy for 5 years^[26]. Recently HRT has also been proven to lower markers associated with cellular senescence after 3 years^[27], suggesting it may lessen the risk of contracting age-related diseases in elderly women.
10. Decreased Gastrointestinal Cancer Risk. While HRT may promote reproductive cancers in susceptible women, its use may be protective against gastrointestinal cancers. In a large-scale study examining just over 290,000 women, 8 years of HRT was associated with a 10% overall reduction in gastrointestinal cancer risk, with special regard towards esophageal, liver, and colon cancer.^[28]

When Can a Woman Start HRT?

A doctor will suggest HRT to women entering menopause who consistently suffer from symptoms that are hard to tolerate. However, many studies have indicated that HRT can be started earlier in order to reduce the risk of symptoms and maximize the benefits.

Starting HRT within 10 years of menopause has been shown to bear the most anti-aging benefit and increase longevity outcomes.^[29] After 10 years from menopause onset, HRT appears to offer no benefit,^[30] and the risks associated were shown to double for many women^[31].

Types of Hormone Replacement Therapy and How They Compare

HRT is offered in a variety of forms, including synthetic and non-synthetic forms, patches, pills, vaginal inserts, rings, creams, sprays and more. Usually, the therapy is started at a lower dose and gradually increased until menopausal symptoms have been contained.

Key differences between the main types of HRT are discussed below.

Synthetic Hormones

While incredibly popular, some synthetic hormones have proven to be far more of a risk than their bioidentical counterparts. Aside from hormones, synthetic compounds have been developed that modulate estrogen receptors in order to promote more favorable outcomes.

Differences between synthetic hormone treatments are discussed below.

Synthetic Estrogens are standard choices for use in both HRT and contraceptives. They are known to possess a similar efficacy to equine and bioidentical estrogens. However, their use has also been associated with more side effects than other estrogens. Data concerning their individual benefits and risks in menopausal women is scarce.

Common synthetic estrogens include^[32]:

• Estradiol valerate has been shown to be tolerated better in women, with fewer side effects by comparison to ethinylestradiol. In young women, estradiol valerate was less inflammatory than ethinylestradiol, with a neutral effect on blood clotting factors, cholesterol^[33] and the ovarian-pituitary axis^[34]. In 50 perimenopausal women, 9 weeks of estradiol valerate was shown to successfully control symptoms and provide benefits, such as increasing sleep quality, enhancing mood, and improving the overall quality of life.^[35]
• Ethinylestradiol has been shown to promote inflammation in skin cells at high doses and may be responsible for increased photosensitivity.^[36] In rats, this form of estrogen in small quantities was shown to promote glucose tolerance, insulin sensitivity, and weight loss.^[37] Extremely low-dose products containing ethinylestradiol (5mcg) are prescribed to menopausal women in the US to control symptoms with minimal side effects^[38]. In younger women, oral formulations can substantially increase blood clotting factors^[39] and may be associated with the increased risk for thromboembolism highlighted in large-scale studies (especially when combined with synthetic progestins).

Selective Estrogen Receptor Modulators (SERMs). Out of all the synthetic treatment options available, SERMs may become some of the most attractive options due to their high selectivity for estrogen receptors in specific tissues. Unfortunately, many available SERMs (including tibolone and tamoxifen) on the market are ineffective for reducing menopausal symptom intensity, do not offer benefits, and may even induce severe side effects.^{[40] [41]}

Progestins are synthetic versions of progesterone. Most studies have proven that progestins promote many of the negative side effects associated with HRT, whether used alone or in combination with estrogens^[42]. Furthermore, most synthetic progestins (especially MPA) are known to increase the risk of contracting breast cancer, cardiovascular disease, heart attacks, strokes,^[43] and endometrial cancers^[44]. Breast cancer remains to be one of the biggest risks associated with progestogen use. One study showed that in women using synthetic estrogen and progestin (MPA) combinations, breast cancer cell growth increased from 2.2 to 9.1% on average, with some women showing a 25% increase.^[45]

Common progestins used in HRT include:

• Medroxyprogesterone Acetate (MPA) is possibly the worst form of progesterone available for use in HRT. Most of the negative reputation of progestins and HRT at large is attributable to MPA. MPA interferes with liver metabolism, increases bodily inflammation, negatively affects cognitive function,^[46] and substantially increases the risk of reproductive cancers in women using it.
• Micronized Progesterone is known to be the safest synthetic progestin^[47]. It was designed in order to bypass the liver, avoid deleterious metabolic effects, and reach peripheral tissues. Micronized progesterone was shown to have a neutral effect on the vascular system^[48] and pose a negligible breast cancer risk, particularly at low doses^[49]. Due to its inability to interfere with liver metabolism, it does not increase the risk for thromboembolism and has been shown to even reduce the risk in some studies^[50]. This form has been shown to stimulate GABA, which may, in turn, enhance sleep and have a calming effect. Despite being a safer alternative, breast cancer risk has been demonstrated to increase after using micronized progesterone for 5-8years.^[51]

Natural Hormones

To be continued in Part 2.