MHT: Timing is critical


Experts agree menopausal hormone therapy (MHT) is safe and effective for women with no absolute contraindications—but timing is critical

Leading menopause experts have welcomed a UK study that suggests the risk between breast cancer and MHT is less than previously reported.

A study published in the British Medical Journal (BMJ) found the most commonly prescribed MHT in Australia was associated with lower risk of breast cancer. Monash University’s Women’s Health Research Program director, and past president of the International Menopause Society, Professor Susan Davis, said the study findings were “incredibly reassuring”.

Prof Davis said for women using oestrogen-only MHT, the study put women’s overall breast cancer risk at 3 per 10,000 women.

“You may have more chance of a car accident. Seriously, it’s more dangerous to walk out of your house,” Prof Davis said.

She said one treatment examined by the authors—oestrogen and dydrogesterone, was found to have no increased risk after five years’ use—and after that the risk was marginal.

“That’s one of the most common combinations we prescribe in Australia—it’s a good news story.”

Jean Hailes endocrinologist and president of the Australasian Menopause Society, Dr Sonia Davison commented that as the study examined a 20-year period, it included some hormone treatments that are either used infrequently or not all. And the most common combinations used by women in the study were medroxyprogesterone or norethistero—which Prof Davis said “we know [can] cause breast cancer”, and are not used in Australia anymore.

She also said different methods of administration were also not assessed separately.

“They don’t separate transdermal from oral—it’s all just lumped together.”

While expert guidance is crucial for each woman considering MHT, Dr Davison said international expert groups agreed that for healthy menopausal women, the benefits of MHT far outweigh the small risks associated with its use.

“It’s a matter for every woman to weigh-up quality of life, bothersome symptoms, bone and cardiovascular health and her own risks of breast cancer, given her individual circumstances and population risks.”

Jean Hailes’ medical director, Dr Elizabeth Farrell, pointed out that it was important to acknowledge “women do get breast cancer” given it is the most common cancer diagnosed in women.

“The crude incidence of breast cancer in one of the cohorts was 33 per 10,000 women years, whereas the crude incidents of women not exposed to HRT was 31.5. People think the balance is always way up on the [MHT] side so that figure is really important,” she said.

Since the 2002 publication of the US Women’s Health Initiative (WHI) study, many women have remained sceptical about the safety of MHT due to fears about a link with breast cancer.

Indeed, a recent Australian study found women had a good understanding of the immediate effects of menopause, but their lack of knowledge of the long-term consequences was concerning. Despite the effectiveness and safety of MHT, the overall attitude to MHT remains negative, the researchers said.

Timing is critical

Award-winning consultant clinical pharmacist, Debbie Rigby, also believes MHT is safe and effective for women with “bothersome symptoms and no absolute contraindications”.

Ms Rigby, who has written extensively on MHT including CPD materials for the AJP, said there are now many options for women that can be tailored to the individual risk factors and preferences.

“MHT is the most effective treatment for the relief of vasomotor symptoms (VMS) of menopause. In the absence of contraindications, a woman should determine her preferred hormone therapy dose, formulation, and duration of use, with ongoing reassessment of risks and benefits, through shared decision making with her clinician. Body-identical transdermal estradiol and micronised progesterone should be offered to most menopausal women, particularly at the menopause initiation. MHT should be used at the lowest effective dose for the shortest time possible. For most women with bothersome symptoms, the benefit of MHT outweighs the risks.”

But she is also highly critical of the way the 2002 WHI study was represented.

“Overreaction and misrepresentation of the findings in the WHI study have resulted in major damage to the health and wellbeing of women experiencing menopausal symptoms,” Rigby told the AJP.

“Menopausal symptoms are known to be very distressing, so effective symptomatic relief should not be denied. There is now a good evidence-based consensus for use of MHT in the first decade after menopause but timing is critical.

“The option for MHT should be individualised, considering risk factors such as age, time since menopause and risk of (venous thromboembolism) VTE, stroke, ischaemic heart disease and breast cancer.

Body-identical hormones (i.e. estradiol, micronised progesterone, dydrogesterone) are TGA-approved products that are chemically and structurally identical to endogenous hormones. Bioidentical products may be promoted as being more ‘natural’, however manmade or synthetic hormones are still used for these compounded products.”

Even though, ‘bioidentical’ is a marketing rather than a medical term, any preference for natural hormones may be met with the same hormones, estradiol and progesterone, that are made during the reproductive years, she added.

Body-identical transdermal estradiol and micronised progesterone are now the preferred treatment choice as they maximise the benefits of hormone therapy while minimising the side effects, she said.

Progesterone

Debbie Rigby noted that the following terms are sometimes incorrectly used interchangeably:

  • Progestogens: are products that bind to progesterone receptors.
  • Progesterone: is a body identical hormone and binds only to progesterone receptors.
  • In vivo, progesterone is produced by the corpus luteum following ovulation.
  • Progestins: are synthetic progestogens, first developed to increase oral absorption. Progestins include norethisterone, levonorgestrel, drospirenone, medroxyprogesterone acetate, cyproterone, dienogest, nomegestro.

“The appropriate dose of progestogen is added to provide endometrial protection if a woman has an intact uterus, unless Conjugated Equine Estrogen (CEE) is combined with bazedoxifene (Duavive).

Bazedoxifene, is a selective [o]estrogen receptor modulator (SERM), and combined with CEE it forms a tissue-selective oestrogen complex. The combination provides endometrial protection without the need for a progestogen. Bazedoxifene has a better risk profile for breast cancer compared to oestrogen–progestin therapy, with a beneficial effect on risk of bone fractures and a neutral effect on blood pressure and lipids.

This may be a preference for women with a family history of breast cancer or a history of cysts or dense breast tissue.

“Progesterone and dydrogesterone bind strongly to the progesterone receptor, with little affinity to other receptors. This is important as other synthetic analogues of progesterone (progestins, progestogens) also bind to the glucocorticoid, mineralocorticoid and androgen receptors, which may lead to unwanted adverse effects such as unfavourable glucose, metabolism, fluid retention, acne and weight gain.

Oral micronised progesterone (Prometrium) often causes drowsiness, which can be a benefit when taken at bedtime. It has a better risk profile for breast cancer compared to synthetic progestogens, and a neutral effect on blood pressure and lipids.”

Oestrogen

The lowest effective dose of oestrogen therapy consistent with treatment goals is recommended, Ms Rigby said..

“CEE, used in the WHI study, is a complex mixture of estradiol, estrone and potent equine oestrogens, androgens and progestogens that are not natural to humans. Natural estradiol is now preferred as it is body identical and can be administered orally, as transdermal patches and gels.”

For women with impaired liver function, hypertriglyceridaemia, diabetes and those at risk of thromboembolic disease, including pulmonary thrombosis, transdermal estradiol preparations are recommended. Transdermal administration facilitates a long-term balance of oestrogen levels and the physiological ratio of the levels of estradiol and estrone.

Importantly, it is the safest type of hormone therapy in women at risk of VTE. Adverse skin reaction from patches occurs in 30-50% of cases; whereas body-identical estradiol gel (Estrogel) has no greater incidence of skin reaction than placebo, Rigby said.

“Regarding the risk of VTE, oestrogen doses used in MHT are far lower than in the oral contraceptive pill – which many women considering MHT have taken for decades. The risk of VTE and ischemic stroke increases with oral MHT, although the absolute risk of stroke with initiation of MHT before age 60 is rare.

Oral oestrogen increases the risk of VTE four-fold; and CEE, with or without medroxyprogesterone acetate, are associated with highest risks. Transdermal oestrogen is not associated with risk of VTE in postmenopausal women. Micronised progesterone and pregnane derivatives (e.g. dydrogesterone, medroxyprogesterone acetate) appear safe with respect to thrombotic risk.”

She also said it is important to remember that oestrogens can be administered safely vaginally.

“It is safe to give with MHT and about 20% of women need both. It may need to be used long-term or lifelong for vaginal dryness and atrophy, long after hot flushes and night sweats have abated.

The dose of vaginal oestrogen is very low (using 10mcg oestrogen pessaries regularly for one year is an equivalent dose to just one 1mg estradiol tablet).3 Women with a history of any type of cancer, including an oestrogen-receptor-positive cancer, can still safely use vaginal oestrogen and continue long term. Many women using vaginal oestrogen should also be recommended to use vaginal moisturisers and lubricants too.

“Vagifem Low modified release pessary formulation is based on a hydrophilic cellulose derived matrix which on contact with moisture hydrates and provides a controlled release of estradiol. It is indicated for treatment of atrophic vaginitis due to oestrogen deficiency in postmenopausal women. Vagifem Low may be used in women with or without an intact uterus—does not need progesterone unless on oral oestrogen with intact uterus.”

Rigby said another option is tibolone: “Tibolone has an oestrogenic effect on vagina, bone and thermoregulatory centres in the brain and has progestogenic and anti-oestrogenic effects on breast and endometrium. Tibolone may be preferred to MHT in women with high breast density, urogenital problems, accelerated bone loss, mood swings and lower sexual drive or sexual dysfunction.” 

Trial targets: perimenopausal depression

Researchers in Melbourne have launched a study to see if an experimental mix of medicines can successfully lower anxiety and lift the mood in women experiencing perimenopause.

Ninety women will take part in the new study which will be led by Professor Jayashri Kulkarni AM and her team at the Alfred Monash Psychiatry (AMP) Research Centre.

Most women reach menopause between the ages of 45 and 55, but the years leading up to menopause can cause symptoms similar to, or even more intense than, menopause. This is due to hormone fluctuations as the ovaries begin to slow down and run out of eggs.

Due to these hormonal changes, the risk of serious depression is increased in perimenopausal women.

Symptoms can include low energy, irritability, paranoid thinking and reduced self-esteem. Many women are treated with standard antidepressants, but often show only little or no improvement.

In Prof Kulkarni’s study, half of the women will be given a combination of bazedoxifene and a conjugated oestrogen, while the other half will be given a placebo.

“This medication is to target the changes to the reproductive hormones, which we think will be a better overall treatment,” explains Dr Natalie Thomas, a research fellow at the AMP Research Centre.

“There is a lot of pre-clinical and clinical work to suggest that oestrogen helps to lift mood. The reason we want to trial this particular drug is that it is tissue selective. It will target the brain.”

Dr Thomas said the researchers have already completed a trial with tibolone, a synthetic steroid with a mixed hormonal profile which showed good results in treating perimenopausal depression.

“It breaks down into oestrogen and we are seeing good results in this group of women,” she said. “The reason we want to try this new medication mix is that it works a little differently. Bazedoxifene is tissue selective—it works in the brain and the bone. It is currently prescribed as Duavive for women in menopausal transition experiencing physical symptoms like hot flushes.

“It is approved by the TGA to treat moderate to severe vasomotor symptoms associated with menopause.
“We are investigating the drug for mental health purposes.”

Dr Thomas said the researchers hope the study will be able to establish if the drug can lift the mood and lower the anxiety levels of affected women. They will use a detailed questionnaire called the MENO-D to track the severity of the illness and to monitor improvements. The women will be tracked for three months.

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