While the risks of unopposed oestrogen are widely acknowledged, important nuances can be missed…

Progestogens are a vital part of Menopause Hormone Therapy (MHT), but they are a complicated set of hormones, irrespective of whether they are ‘natural’ or synthetic. Finding the right one requires careful evaluation by the clinician, says Rod Baber, Professor of Obstetrics and Gynaecology at the University of Sydney and Head of Menopause and Menstrual Disorders Clinic at Royal North Shore Hospital.

The nomenclature

Progestogen is the umbrella term for both synthetic progestins and ‘natural’ or ‘body/bio identical’ progesterone.

Progestogen is the name given to any steroid hormone that attaches to or activates the progesterone receptor. “That includes natural progesterone and all the synthetic progestogens, which, to complicate things and make people more confused, are called progestins,” Professor Baber says.

What do progestogens do?

“Think about what happens in a normal menstrual cycle,” Professor Baber says. “It’s the simplest way to understand what progestogens do, particularly progesterone,” he says.

“In the first half of the menstrual cycle, the ovary produces just oestrogen. And that causes the lining of the uterus, the endometrium, to proliferate. Ovulation occurs in mid cycle—an oocyte is released and the corpus luteum in the ovary produces progesterone. Progesterone is only produced if ovulation occurs, and its major physiological role is to convert proliferative endometrium into secretory endometrium in preparation for a pregnancy.”

Progesterone does two critical things

1. It enables a pregnancy to progress by changing proliferative endometrium to secretory endometrium, which enables implantation of the embryo and maintains the pregnancy.

2. It controls the regularity of the menstrual cycle. If a pregnancy doesn’t happen, progesterone production stops in the second half of the cycle and menstruation occurs. So therefore, if a woman ovulates every month, she will have a regular period. But, if she doesn’t ovulate, the proliferative endometrium continues to grow because of the effects of ‘unopposed’ oestrogen.

The role of progesterone in endometrial cancer

The effect of unopposed oestrogen on the lining of the womb (the endometrium) is to initially cause proliferation, then simple hyperplasia (overactivity), then complex hyperplasia and then complex hyperplasia with atypia, which is precancerous and generally irreversible.

This is what happens when women of reproductive age have a long phase without ovulation (the classic example is women with PCOS). It also happens when post-menopausal women with an intact uterus are given unopposed oestrogen for a prolonged time. A large randomised clinical trial in the USA (the PEPI Trial) found that after three years, approximately two-thirds of women had endometrial hyperplasia, and for 12%, it was pre-cancerous. No cancer was seen in that trial.

“That’s why progesterone or progestogens must be used alongside oestrogen in women who are prescribed MHT to relieve menopausal symptoms. The progestogen is used to protect the endometrium,” Professor Baber explains.

Which progestogen to choose?

Micronized progesterone and the stereoisomer dydrogesterone are considered safest in terms of breast cancer and cardiovascular disease risk.

Micronized progesterone is usually taken orally. It has been successfully used off-label vaginally in women who don’t tolerate oral progesterone (transdermal use hasn’t been successful).

Note that topical creams containing progesterone have not been found to offer reliable endometrial protection.

Norethisterone combined with oestrogen in a patch has been shown to be effective, but is associated with somewhat more unplanned spotting than oral therapy.

Synthetic progestogens act on different steroid hormone receptors depending on their derivation, which is why some people may fare better on one type over another.

The original progestins were derived from androgen precursors, later forms came from 17 hydroxy progesterone, and the most recent one is derived from drospirenone.

For example:
– androgenic progestogens like norethisterone also bind to androgen receptors and weakly to oestrogen receptors.
– MPA, medroxyprogesterone binds to glucocorticoid receptors.
– those derived from testosterone bind to some degree with androgen receptors.
– those derived from 17 hydroxy progesterone, which is a corticosteroid precursor bind to glucocorticoid receptors.
– those derived from Spironolactone can bind and compete at mineralocorticoid receptors.

It’s thought that the binding is responsible for differences in risk for breast cancer and thromboembolic disease.

Unwanted effects

“All of these compounds will produce what you might call a family of effects including headaches, mood changes, irritability and breast tenderness. These will vary from progestogen to progestogen and also between women. Some are better than others, but on the whole, progesterone is the best tolerated of the lot,” Professor Baber says.

Progestogenic side effects and doses can make starting MHT difficult for some women and may also discourage some doctors from prescribing it.

One solution is to choose one of the combination preparations which are available to peri and postmenopausal women.

Preformulated combined preparations have been tested very thoroughly to make sure that the right dose of progestogen is combined with the right dose of oestrogen. “For many women, they will provide a simple, safe, reliable solution,” Professor Baber says.

For most recently postmenopausal women, with no underlying risk factors, oral preparations are fine.

For women with increased risks (such as older age, cardiovascular disease, diabetes, obesity, smoking and family history of VTE), transdermal delivery should be used where possible.

Sometimes the best combination for symptom relief and minimal side effects will require a separate oestrogen and progestogen.

“When this is done it is very important to explain to the woman exactly how and why she needs to take both the oestrogen and progesterone component of her combined MHT,” Professor Baber says.

Generally natural progesterone is preferred to synthetic progestins because evidence suggests less thromboembolic risk and less breast cancer risk when combined with oestrogen.

Patient preference is another factor

“I always start off by explaining to patients that we think the best combination is body identical oestrogen and body identical progesterone, and I tell them why. But I also explain that the risks associated with any form of hormone therapy in the short term are very, very low,” Professor Baber says.

“If we look at the Women’s Health Initiative, where an oestrogen was used with a synthetic progestogen, the risk of a thromboembolic event overall in that study was an extra one case per 1000 women per year and was not seen for the duration of the trial in women who were in their 50s.”

“The risk of breast cancer was an eight extra cases per 10,000 women. And again, with 20 years of follow up, we know that that wasn’t associated with any increase in mortality from that dreadful disease.”

“So, I do always encourage the use of body identical hormones. And I certainly push hard for transdermal hormones in women who I consider to be above average risk for migraines, thromboembolic disease, hypertension, obesity, smoking and so on. But otherwise, I try to take them on a journey with me and work out what’s going to be the combination they will be happiest using, will be safe for them and is affordable.”

Recommended resources:
• Australasian Menopause Society
• Jean Hailes Foundation