In the previous post, I briefly surveyed the history of menopausal hormone therapy (MHT) since the 1950s, analysed the rise of 'the perimenopause' as a textbook example of disease mongering, and sorted the laundry list of symptoms often ascribed to 'the perimenopause' into three categories: those symptoms that are definitively linked to the dramatic changes in reproductive hormones that occur during the menopausal transition; those that may be linked to hormonal changes; and those that are not, or are probably not, caused by hormonal changes but instead by aging and/or poor health and/or psychosocial issues.
I spent many hours combing through the medical literature to sift the claimed symptoms of perimenopause into these three piles, for two reasons: Firstly, to illustrate how disease mongering works - in this case, by expanding the diagnostic boundaries of a 'condition' (which in point of fact is not a condition but a life stage), until just about anything that might befall a mid-life woman is now considered to be evidence that she is suffering from 'the perimenopause'. Secondly, because a logical starting point for discussing which symptoms might be relieved by MHT, is to identify those that are driven by hormonal changes. In theory, these should respond favourably to MHT. As it turns out, there are a few surprises, but we'll get to that shortly.
As a reminder, the following symptoms and signs1 have consistently been demonstrated to be directly linked to the decline in estrogen and progesterone levels that occur as women’s ovarian function winds down, and eventually ceases - that is, they are due to the menopausal transition rather than temporally associated with it:
Vasomotor symptoms - hot flushes/flashes and night sweats.
Adverse changes in blood lipids and lipoproteins - increased total cholesterol, low density lipoprotein cholesterol (LDL-C), and apolipoprotein B, along with increased levels but decreased functionality of high density lipoprotein cholesterol (HDL-C), collectively leading to an increased propensity to form atherosclerotic plaque, which in turn leads to coronary artery disease, peripheral arterial disease, dementia, and chronic lower back pain and intervertebral disc degeneration.
Adverse changes to blood vessels - thickening of arterial walls (indicating plaque accumulation), increased arterial stiffness and impaired function of the endothelium – the lining of the artery wall, collectively leading to increased blood pressure, ‘stickier’ blood and increased plaque formation.
Adverse changes in body composition - increased total body fat, increased visceral adipose tissue (deep belly fat), and decreased muscle mass.
Diminished bone mineral content and toughness - adverse changes to bone quantity and quality that increase the risk of fracture.
Vaginal dryness and atrophy - thinning and drying of the vaginal wall, leading to burning, itching and pain during sex.
The following symptoms may be caused by the hormonal fluctuations that characterise perimenopause, but the evidence is not conclusive; they may instead be caused by aging, stress, social or personality factors:
Sleep disturbances - excluding those related to night sweats.
Depression in women with no prior history of depressive symptoms. There is no increased risk of first onset of major depressive disorder (MDD) in perimenopause, but women who have previously experienced MDD are prone to relapse during this life stage.
Anxiety, irritability, loss of libido, fatigue - these symptoms are common in women across the lifespan, and their relationship with perimenopause is uncertain.
And finally, the following signs and symptoms are not attributable, or probably not attributable to the hormonal milieu of perimenopause, but are more directly attributable to aging and/or poor health and/or psychosocial problems:
Blood pressure, insulin, glucose, Lp(a), and hemostatic and inflammatory factors
Low sexual desire, arousal and emotional satisfaction, aside from that related to vaginal dryness and pain.
Which of these symptoms and signs are reliably relieved by MHT, and which are not?
The following complaints are helped by menopausal hormone therapy:
1. Vasomotor symptoms
When it comes to relieving hot flushes and night sweats, menopausal hormone therapy works very well - although not for every woman. The Endocrine Society drew on evidence from clinical trials and from a 2004 Cochrane review to conclude that "MHT reduces hot flash frequency by approximately 75% and severity by 87%, compared with 50% with placebo." (Actually, the Cochrane review found that women assigned to placebo had a 58 per cent reduction in hot flush frequency.) According to Cochrane, this equates to 18 fewer hot flushes per week. Higher doses give greater relief from vasomotor symptoms (three fewer hot flushes/night sweats per day for standard-dose estrogen vs one to two fewer per day for low-dose estrogen... but higher doses also lead to more adverse effects such as breast tenderness and nausea. For around seven in ten women, MHT eliminates hot flushes.
Unsurprisingly, MHT helps with sleep disturbance related to vasomotor symptoms; if you're having fewer and less severe episodes of night sweats, you're going to sleep a heck of a lot better than if you're waking up in a cold sweat multiple times each night, having soaked your bedclothes! However, MHT does not benefit insomnia that's unrelated to hot flushes and night sweats.
Also unsurprisingly, MHT can help to relieve depressive symptoms in women with troublesome vasomotor symptoms. Once again, if you're debilitated by hot flushes all day and night sweats all night, you're not going to be a happy camper, so getting relief from these bothersome symptoms will help to brighten your mood.
2. Vaginal dryness and atrophy, and pain during sex
At higher doses, systemic estrogen (i.e. taken by mouth or applied as a patch or gel) effectively relieves vaginal dryness and atrophy and improves the symptoms of overactive bladder and recurrent urinary tract infections. However, topical estrogen products such as creams, rings, gels and suppositories work just as well, at much lower doses and with less risk of adverse effects than systemic estrogen. And non-hormonal vaginal lubricants are just as effective at relieving pain during sex that's due to vaginal dryness, without any risk of hormonal side effects.
For women with severe vaginal symptoms who are more than ten years post-menopause and who have not already been on systemic MHT, topical estrogen products are the safest choice, as the Women's Health Initiative trial found that commencing systemic hormone therapy more than ten years after the last menstrual period caused more harm than good.
3. Bone loss
MHT reduces bone loss, and decreases the rate of osteoporosis-related bone fractures, although this benefit is only seen in women older than 70 or who are more than 20 years post-menopausal, in keeping with the age at which such fractures typically occur. To put some numbers on it, after 7 years' use of estrogen-only MHT, the risk of a clinically-apparent fracture (i.e. not just asymptomatic but detected on x-ray) dropped from 141 per 1000 to between 92 and 113 per 1000, while 5.6 years' use of estrogen plus progestin MHT decreased fracture risk from 111 per 1000 to between 79 and 96 per 1000.
4. Body composition changes
MHT has a minor effect on body composition changes. By helping to preserve muscle mass, it may limit perimenopausal weight gain.
The following complaints are not helped by menopausal hormone therapy:
1. Depression and anxiety
As mentioned above, depressive symptoms in women with bothersome hot flushes and night sweats are relieved by MHT. However, neither bioidentical nor transdermal MHT is effective for generalised depressive symptoms, and it is also not effective for treating major depressive disorder or for preventing its recurrence in women who had previously experienced this condition.
2. Aches and pains
Given that stiff and painful joints and muscles are symptoms of aging, along with physical inactivity and sedentary behaviour (prolonged sitting), rather than of perimenopause itself, it's not shocking that MHT fails to relieve aches and pains.
3. Cognitive impairment and decline
There is no doubt that fluctuations in estrogen and other reproductive hormones during perimenopause cause cognitive impairment in a significant proportion of women, affecting learning capacity and memory. These cognitive deficits resolve as the menopausal transition progresses. Persistent decline in cognitive function only becomes apparent well after menopause, and this age-related decline is exacerbated by obesity, metabolic dysfunction, high blood pressure and financial hardship - none of which are responsive to MHT!
MHT may relieve short-term perimenopause-associated cognitive symptoms, but it has no lasting benefits on cognition; women who began using estrogen therapy (with or without a progestin) in their early 50s did not experience any benefits in memory or other aspects of cognition by the time they reached their late 50s and mid-60s; in fact, women on estrogen-only therapy had slightly worse verbal fluency scores. And in women who commence estrogen therapy (with or without a progestin) at age 65 and older, brain volume decreases while verbal memory worsens and the risk of cognitive decline and dementia increase over time, eventually doubling in women taking estrogen plus progestin MHT. According to Cochrane's 2017 systematic review, after 7 years' use of estrogen plus progestin, women's risk of dementia rose from 27 per 1000 to between 38 and 60 per 1000.
4. Coronary heart disease
Although estrogen does decrease total and LDL-cholesterol, increase HDL-cholesterol and improve vascular function, neither estrogen-only MHT nor estrogen plus a progestin decreases the risk of coronary heart disease events. Many proponents of MHT have claimed that the lack of cardiovascular benefit only applies to older women who commence therapy many years after menopause. But women randomised to receive either oral or transdermal estrogen plus oral progesterone, commencing six months to three years after their last menstrual period, had the same rate of progression of atherosclerosis in their carotid arteries as women taking placebo.
Outcomes do vary between estrogen-only vs estrogen plus progestin MHT. That 2017 Cochrane review concluded that after one year of use, women taking estrogen plus progestin therapy would increase their risk of a coronary event from 2 per 1000 to between 3 and 7 per 1000; estrogen-only therapy did not increase the risk of a coronary event.
Oral estrogen may be more hazardous to the cardiovascular system than transdermal estrogen (i.e. patches and gels); a study of Swedish women found that those taking oral estrogen plus progestin had a higher risk of ischaemic heart disease, and those taking oral estrogen with or without progestin had a higher risk of venous thromboembolism, while no excess risk was seen in women using transdermal estrogen. (On the other hand, a meta-analysis found no significant difference in risk of heart disease between oral and transdermal MHT.) Obviously, no excess risk doesn't mean there was any cardiovascular benefit, simply that there was no apparent harm.
5. All-cause mortality
There's no difference in all-cause mortality between women taking either estrogen-only or estrogen plus progestin - that is, MHT does not make women live any longer. (Not much of a fountain of youth then, I guess.)
Conditions in which outcomes differ depending on the type of MHT:
1. Breast cancer
Women receiving estrogen plus progestin MHT have a slightly elevated risk of invasive breast cancer (0.5 per cent higher absolute risk) but their risk of dying of breast cancer is not significantly increased. For women on estrogen-only MHT, the risk of invasive breast cancer, and breast cancer mortality, is actually lower.
2. Colorectal cancer
In contrast to the breast cancer findings, estrogen plus progestin MHT slightly decreases the risk of colorectal cancer (however, the cancers were detected at a more advanced i.e. less treatable stage), while estrogen-only MHT has no effect.
Risks of MHT
1. Stroke:
Women taking either estrogen-only or estrogen plus progestin have a roughly 36 per cent higher relative risk of having a stroke (increase in absolute risk of 0.6 per cent).
2. Thromboembolic events:
The risk of venous thrombosis, deep vein thrombosis (DVT) and pulmonary embolism is roughly doubled in women taking estrogen plus progestin; estrogen-only MHT increases DVT risk. The 2017 Cochrane review concluded that after one year of use, women taking estrogen plus progestin therapy would increase their risk of venous thromboembolism from 2 per 1000 to between 4 and 11 per 1000. Estrogen-only therapy also increased venous thromboembolism, with the risk compounding over time: from 2 per 1000 to 2 to 10 per 1000 after one to two years' use, and from 16 per 1000 to 16 to 28 per 1000 after seven years' use. Oral estrogen may be more hazardous than transdermal, when it comes to thromboembolic events.
3. Gallbladder disease:
Both estrogen-only and estrogen plus progestin MHT increase the relative risk of gallbladder disease by roughly 60 per cent (increase in absolute risk of 0.47-0.55 per year). In women taking estrogen plus progestin, the risk of gallbladder disease after 5.6 years' use rose from 27 cases per 1000 to between 38 and 60 per 1000; in women taking estrogen-only MHT, 7 years of use bumped up gallbladder disease incidence from 27 per 1000 to between 38 and 60 per 1000.
4. Urinary incontinence:
Women using both estrogen-only and estrogen plus progestin are more likely to develop bladder control issues, and this increased risk persists after stopping MHT.
5. Suicide:
In a longitudinal study of over 290 000 US veterans, women taking MHT were more likely to attempt and complete suicide over the next 4.5 years, even after statistical adjustment for age, race, and medical diagnoses. The association with death by suicide persisted after further adjustment for psychiatric comorbidity and psychoactive medications, indicating that the association between suicide risk and MHT use was probably not reverse causation (i.e. worse mental health causing both more MHT use and higher suicide risk).
Is custom-compounded MHT any better?
The Endocrine Society, American Association of Clinical Endocrinologists and American College of Endocrinology all advise against the use of custom-compounded hormone therapy (often dubbed 'bioidentical' by proponents), because of the lack of quality control and the absence of scientific studies demonstrating safety and efficacy. Furthermore,
"Proponents of custom-compounded hormone therapies often advise measuring salivary hormone levels to monitor therapy. However, scientific evidence is lacking to justify salivary measurements due to inter- and intra-assay variability, variable salivary flow rates dependent upon hydration, food intake, and other factors, and the inability to predict the pharmacokinetics of a custom-compounded hormone dose in a manner that would allow for valid salivary sampling."
Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline
In other words, practitioners who supposedly tailor your MHT prescription precisely to your current hormone levels are - wittingly or unwittingly - engaging in an elaborate con.
OK... so what do I do with all this information?
As I'm sure you've gathered by now, women who are suffering severe symptoms during perimenopause have some very complicated decision-making to do. Despite the renewed hype over menopausal hormone therapy, its benefits are extremely limited: it does very effectively relieves vasomotor symptoms (hot flushes and night sweats) and associated sleep disturbances and depressive symptoms, eases vaginal dryness and painful sex, reduces bone loss and fracture risk quite substantially, and slightly ameliorates negative changes in body composition. These benefits come at the cost of increased risk of stroke, thromboembolic events, gallbladder disease, urinary incontinence and possibly suicide; and in some subgroups of women, increased risk of breast cancer, cardiovascular disease, cognitive decline and dementia.
Clinical practice guidelines issued by the Endocrine Society reflect this complexity, advising women to discuss the risks and benefits of MHT with their doctor. If their medical history does not rule out hormonal treatment, and their vasomotor symptoms are bothersome, oral or transdermal estrogen-only (for hysterectomised women), or estrogen plus micronised progesterone or progestin therapy (for women with an intact uterus) should be used for the shortest total duration required to achieve treatment goals, with reviews conducted at least annually. Cochrane concurs, stating that the net harms of short-term use in relatively healthy women are small. (It's worth noting, however, that a Danish study found that even short-term use of estrogen plus progestin therapy close to the age of menopause, was associated with increased risk of all cause dementia and Alzheimer’s disease.)
Women should not be advised to take MHT for prevention of chronic conditions (even osteoporotic bone fracture) given the net benefits and harms.
Are there any alternatives to MHT that actually work?
But what if you're having bothersome vasomotor symptoms, and you can't - or don't want to - take MHT? Are there any non-hormonal and/or non-medical options that genuinely relieve the distressing symptoms of perimenopause? We'll answer that question in Part 3 of the the Menopause Files - stay tuned!
And finally, this post has taken approximately 20 hours to research and write. If you feel you’ve benefited from reading it, please consider a paid subscription to help me continue this work:
For information on my private practice, please visit Empower Total Health. I am a Certified Lifestyle Medicine Practitioner, with an ND, GDCouns, BHSc(Hons) and Fellowship of the Australasian Society of Lifestyle Medicine.
A symptom is a subjective experience reported by the patient, such as pain, fatigue, or bloating. A sign is an objective finding that a healthcare professional can observe or measure, such as elevated blood pressure, abnormal blood test results or increased visceral fat deposits.
Thank you for your thorough research on this topic. The interesting benefit that I have noticed from starting HRT is that I can sweat again. I did not ever experience hot flashes but I noticed I lost the ability to sweat during hard workouts and my heart rate would be strangely high for my perceived effort. Not sure how long I will continue HRT but wanted to share an odd symptom and resolution.
Not surprising that estrogen plus synthetic progesterone (progestin) would cause problems. Why not discuss bio identical estrogen taken with bio identical progesterone?