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  • Jonathan Raas

HRT (Hormone Replacement Therapy) advantages and risks.



Today I would like to inform you, not only about the many advantages but also about the possible risks of HRT (Hormone Replacement Therapy).

It is of utmost importance to be aware that HRT can relieve specific problems in one woman, and the identical HRT would not affect another with the same symptoms. For some, HRT can be lifesaving and for others lethal.


Hormone therapy is the most effective treatment for vasomotor symptoms, such as profuse heat accompanied by sweating and flushing, and genitourinary syndrome, which we will discuss later. Because these are symptoms readily noticed by the woman, this would give her the wow effect when we start HRT (Hormone Replacement Therapy).

These symptoms are significant because they influence the immediate daily quality of life but represent a minor fraction of the harm provoked by the lack of hormones. I like to compare it to an iceberg, you can't miss the 10% sticking out of the water, but it is the 90% you don't see that you are unaware of.

The risks of hormone therapy differ depending on the type, dose, duration of use, route of administration, timing of initiation, and which hormones we prescribe. Treatment should be individualized using the best available evidence to maximize benefits and minimize risks, with a periodic revaluation of the benefits and risks of continuing therapy.

That is why before starting HRT, we at PROFEMINA need to see this person; we need to know her medical history. She needs a recent annual check with a smear test, ultrasound of the uterus and ovaries, ultrasound of the breast and a mammogram. We would need a basic and sometimes a specific blood/urine analysis before deciding the best HRT for this woman.



ADVANTAGES


Vasomotor Symptoms (VMS)

Usually described as (night) sweats, hot flashes, and flushes. These symptoms are associated with diminished sleep quality, irritability, difficulty concentrating, reduced quality of life and poorer health status.

HRT is considered the most effective treatment


Prevention of Bone Loss

Hormone therapy has been shown to prevent bone loss and reduce fractures in postmenopausal women without osteoporosis. Discontinuing hormone therapy results in rapid bone loss.

We prefer non-oestrogen medications for the treatment of existing osteoporosis.



Joint Pain

Women in the WHI and other studies have less joint pain or stiffness with hormone therapy compared with placebo.


Sarcopenia - decrease in muscle mass and muscle strength

Frailty is associated with falls, hospitalization, disability, and death.

Hormone therapy in postmenopausal women provides a benefit in maintaining or increasing muscle mass and related connective tissue and improving strength and posttraumatic or post-atrophy muscle recovery when combined with exercise.


Premature Menopause

Some women will experience an early onset of menopause. That might be due to an operation (removal of both ovaries) or primary ovarian insufficiency. Health benefits have been shown for menopause symptoms and prevention of bone loss and, in observational studies, heart disease and cognitive decline or dementia.


Genitourinary Symptoms

Meant is the thinning and drying of the vaginal walls and vulva accompanied by inflammation and distressing urinary symptoms. It is due to the deficiency of oestrogen. Hormone therapy effectively treats symptoms of vulvovaginal atrophy and menopause-related dyspareunia (painful intercourse).


Sleep Disturbances


After menopause, sleep disturbances are common, and they tend to begin in perimenopause. Sleep disruptions are strongly associated with (night) sweats, hot flashes, flushes, and a decreased quality of life. Poorer sleep quality is associated with mood fluctuations, memory problems, metabolic syndrome, obesity, and other cardiovascular risk factors. Short (or very long) sleep duration, poor sleep quality, and insomnia are associated with greater cardiovascular disease (CVD) risk.

HRT may improve chronic insomnia in menopausal women if the condition is due to hormonal changes.


Sexual Function

Hormone therapy and low-dose vaginal oestrogen improve sexual problems by increasing lubrication, blood flow, and sensation in vaginal tissues. Studies have not found a significant effect of oestrogen or progesterone on sexual interest, arousal, and orgasmic response. In this case, we would substitute other hormones like Testosterone or DHEA.


Skin and Hair

Oestrogen therapy appears to have beneficial effects on skin thickness, elasticity and collagen when given at menopause.

Changes in hair density and female pattern hair loss worsen after menopause. Hormones have an intimate relationship with hair growth. Oestrogen promotes hair growth. Studies have demonstrated that a decrease in estrogen results in hair loss. Oestrogen seems to aid hair growth by extending the anagen phase of the hair growth cycle.

Androgens are principal regulators of normal human hair growth. The precise mechanisms of hormonal modulation of the hair cycle remain to be elucidated.


Eyes

Hormone therapy appears to decrease the risk of specific macular degeneration.

Oestrogen therapy appears to reduce intraocular pressure and mitigate the risk of open-angle glaucoma in Black women.

There is evidence of positive hormone therapy effects on cataracts, optic nerve disease, and dry-eye disease.


Quality of Life

We define Quality of Life as an overall assessment of one's life relating to one's goals and expectations. Quality of life, if applied to one's mental and physical health, is termed health-related quality of life; if explicitly used to menopause, it is termed as the menopause-specific quality of life, which emphasizes the bother and interference of menopause symptoms.

Hormone therapy immensely improves the menopause-specific quality of life in women experiencing menopause symptoms.


Liver

In women with hepatitis C and fatty liver, we observe a slower progression of fibrosis with hormone therapy.


Metabolic syndrome and diabetes

In the WHI study, women receiving continuous-combined conjugated equine oestrogens and MPA (a progestin) had a statistically significant 19% reduction in the incidence of type 2 diabetes.

As prescribed in our clinic, HRT reduces multiple components of the metabolic syndrome; the incidence of type 2 DM decreased by 30%. The benefit reverses when hormone therapy is discontinued.


Weight and body composition

The menopause transition is associated with increased body fat and decreased lean body mass, which increases the fat-to-lean ratio.

Although hormone therapy may help attenuate abdominal adipose accumulation and weight gain associated with the menopause transition, the effect is negligible.


Cognition

The critical window or timing hypothesis holds that oestrogen can confer cognitive benefits if given early in the menopause transition, but that later use is neutral or detrimental. The healthy-cell bias hypothesis holds that oestrogen confers cognitive benefits when the neural substrate is "healthy" but not diseased.


Alzheimer's Disease

Four observational studies support the opinion that the timing of hormone therapy initiation is a significant determinant of Alzheimer's disease risk, with early initiation lowering risk and later initiation associated with increased risk.

Eighteen-year follow-up data from the WHI showed a reduction in Alzheimer's disease mortality in women randomized to hormone therapy.


All-Cause Dementia

Initiating hormone therapy in women aged older than 65 years increased the risk for dementia, with an additional 23 cases per 10,000 person-years seen in women randomized to CEE plus MPA in the WHI Memory Study.

As mentioned in cognition, we can expect benefits of HRT when initiated early in healthy individuals, and it might be harmful in women when we pass the window of opportunity.

In our clinic, we define this window of opportunity as 6 years after the onset of menopause, as opposed to what is usually considered 10 years in American literature.

The effect of hormone therapy may be modified by baseline cognitive function, with more favourable results in women with normal cognitive function before hormone therapy initiation.


Depression

Depressive symptoms worsen as women transition through menopause.

Vasomotor symptoms increase the risk for elevated depressive symptoms because of nocturnal VMS and sleep interruption. On a day-to-day basis, VMS co-occur with a negative mood and predicts a negative attitude the next day. Vasomotor symptoms appear to be more strongly associated with the onset of depressive symptoms than depressive disorders.

For perimenopause women with depression, there is evidence that HRT improves depressive symptoms to a degree similar to antidepressant medications. Oestrogen therapy does not appear to be effective in treating depressive disorders in postmenopause women, suggesting a window of opportunity in perimenopause.

There is evidence that HRT enhances mood and improves well-being in non-depressed perimenopause women.


Cardiovascular Disease and All-Cause Mortality

Please note that our clinic defines the window of opportunity as 6 years after the onset of menopause.

In the "Early Versus Late Intervention Trial” with oestradiol plus progesterone, hormone therapy (HRT) reduced subclinical atherosclerosis progression measured by carotid artery intima-media thickness after a median of 5 years when initiated within 6 years of menopause onset but not when started 10 or more years afterwards.

A 2015 Cochrane review found that hormone therapy initiated fewer than 10 years after menopause onset lowered coronary heart disease (CHD) in postmenopausal women (RR: 0.52)

It also found a reduction in all-cause mortality (RR: 0.70).

It found no increased risk of stroke.

For women who initiated hormone therapy more than 10 years from menopause onset or aged older than 60 years, this Cochrane meta-analysis found no evidence that hormone therapy had any effect on CHD (RR, 1.07). There was an increased risk of stroke (RR: 1.21) and venous thromboembolism VTE (RR: 1.96).

A 2020 systematic review and meta-analysis found that HRT elevated the risk of venous thromboembolism (VTE) in women who initiated hormone therapy older than 60 or 10 years after menopause (RR: 1.79). They found a null effect or even less risk in women who began hormone therapy younger than 60 or within 10 years of menopause (RR: 0.69).


Cancer

Breast cancer: I refer to my article “Menopausal hormone therapy: why we should no longer be afraid of the breast cancer risk. “The HRT we prescribe does NOT higher the risk NOR does it lower the risk. HRT does reduce the risk of dying because of breast cancer.

Endometrial cancer: Oestradiol-only replacement will higher the risk. Progestogen used with oestradiol, continuously or cyclically for 10 to 14 days monthly, significantly reduces this risk.

Low-dose vaginal oestrogen treatment does not appear to increase endometrial cancer risk.

In other words, to reduce the risk of endometrium cancer compared to women not using HRT, a progestogen is essential.

Ovarian cancer: Oral contraceptives are associated with significantly reducing ovarian cancer risk. HRT does not have any influence.

Colorectal cancer: Risk factors include physical inactivity, obesity, smoking, and decreased use of screening strategies, which may be more likely in hormone therapy nonusers. In observational studies, combined Oestrogen – Progesterone Therapy and Oestrogen-only are associated with reduced colorectal cancer risk and mortality.

Lung cancer: Hormone therapy appears to have an overall neutral effect on lung cancer incidence and survival.


DISADVANTAGES


HRT has been linked to cardiovascular risks, such as heart disease, stroke, and blood clots.

Before starting any HRT, we should carefully evaluate these risks.

Hypertension is not a contraindication if successfully treated and monitored.


After Cancer: breast -, endometrium – and ovarian cancer are considered possibly hormone sensitive. Although HRT (as we usually prescribe) is not the root cause of the malignancy, hormones can worsen the prognosis after primary therapy.

Before starting HRT, it is essential to have a full Well Woman Check.

Regular (yearly) checks are advised.


Postmenopause use of oestrogen is associated with an increased risk of gallbladder stones, gallbladder infection, and cholecystectomy (surgical removal of the gallbladder). The transdermal route of administration, which bypasses first-pass metabolism of the liver, has been associated with less risk of gallbladder disease in observational studies. No associated risk of biliary cancer has been demonstrated.

CONTRAINDICATIONS

Untreated hypertension.

Active or recent arterial thromboembolic disease.

Previous or current venous thromboembolism, unless on anticoagulation treatment.

Active liver disease with abnormal liver function tests.

Undiagnosed vaginal bleeding or untreated endometrial hyperplasia.

Known or suspected Hormone Receptor Positive cancer.

Current, past or suspected breast cancer.

Certain specific conditions as:

Porphyria cutanea tarda

Dubin-Johnson and Rotor syndromes


This article is mainly based on the following literature:


1. NAMS POSITION STATEMENT

The 2022 hormone therapy position statement of The North American Menopause Society

Menopause: The Journal of The North American Menopause Society

Vol. 29, No. 7, pp. 767-794

© 2022 by The North American Menopause Society


2. NICE guideline [NG23] Menopause: diagnosis and management; https://www.nice.org.uk/guidance/ng23




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