HRT is prescribed as oestrogen + progesterone. The ”lead” hormone is oestrogen and a progestagen (either as progesterone or synthetic progestin) is added to counterbalance the oestrogen, as occurs in nature.

In this post we discuss oestrogen, following blog posts lead into progestangens. To look at doses of oestrogen in HRT, we need to go back to the menstrual cycle, as HRT doses and formulations are derived from this.

The menstrual cycle is divided into two phases; the follicular phase where oestrogen dominates and the luteal phase where progesterone reigns supreme. In a typical ovulatory cycle, estradiol is at it’s lowest at the beginning of the cycle, rising to it’s peak in the days leading up to ovulation. Following ovulation oestrogen sharply declines entering the luteal phase,giving way to progesterone’s time to shine. In fact during this phase, Progeterone levels are approximately 100x greater than oestradiol. That is, estradiol serum concentrations exist in the pico-molar range(pmol), whereas progesterone serum concentrations are found in the nano-molar(nmol) range.

During the mid-luteal phase, progesterone levels above 25 nmol/l indicate successful ovulation. Oestrogen climbs again in the luteal phase, as shown in image(below) but never to pre-ovulation levels.

Taking all this into account, the amount of oestrogen in blood across the entire cycle ranges from as low as 70pmol/L to as high a 1400 pmol/l creating an average of 350pmol/L, which is approximately (of course it’s approximate as there is huge scope for individuality within these ranges & phases) the blood level achieved with a 100mcg HRT patch( which is classified as a “high” dose- more on classification of doses to come).

Is 100mcg Patch the starting point for all?

In situations such as POI or surgical menopause before 40, women are prescribed a 100 mcg oestradiol patch (or oral equivalent). In this situation, the goal is to replicating the menstrual cycle, and to replace a true deficiency. In other words the ovaries have ceased production, years or decades too soon and this IS a hormone deficiency. This is very different to , the natural age-appropriate transition into perimenopause and following graduation into menopause, which is not a state of deficiency and as such oestrogen does not need to be provided at this level to “treat” hot flushes & night sweats (the licensed purpose of HRT) or to protect bones.

What are the forms of oestrogen available in HRT?

These are the different forms; CEE (conjugated equine estrogen), 17b estradiol, Estradiol valerate, Estradiol hemihydrate and Estriol.

CEE - is conjugated equine estrogens, sold under the brand name Premarin, delivered orally and very rarely if ever prescribed now, as it carries risks of increased risk of Venous Thromboembolism events, and cholelithiasis/ gall stones .

CEE has been superseded by the following forms of body identical oestrogen(oestradiol):_

17b estradiol is the prefered/ gold standard body and bio-indetical oestogen, available in patches, cream, gels, spray.
estradiol hemihydrate is a micronised form ( reduced to a fine powder & pill delivery) of body identical17b estradiol, available in tablet, gels, spray and patches.
Estradiol valerate is classified as a “prodrug” of estradiol, and also considered as a bioidentical form of oestrogen.
Estriol, also spelled oestriol, is a weak “natural”/ body and bio identical oestrogen, used solely vaginally.

Having established that older style CEE under the brand name Premarin, is not the preferred option , and has been superceded by body and bioidentical formulations, we need to be thinking about the delivery method they can be prescribed as;

Orally > tablets as oestrogen only or combined with a progestagen.

Transdermal > patches as oestrogen only or as a combination product with a progestin

Transdermal > gel, cream & spray as oestrogen

Subcurtaneous > body-identical oestrogen pellets/implants inserted into the fat under the skin (usually in the abdomen or the buttock) where they become absorbed. The hormones are then released slowly over a 4-6- month period. Mosty used for POI and surgical menopause.

Vaginal > ring , tablet & cream as oestrogen . Used for vaginal dryness, inflammation & itching. Acts locally in the vagina to maintain the adequate levels of oestrogen to relieve these symptoms, not treat neaurologicaly symptoms of menopause such as hot flushes, low mood and night sweats.

And for completeness, because I am discussing delivery systems,

Intrauterine > intrauterine system (IUS) delivering progestin only

Doses of oestrogen therapy

The doses of body identical oestrogen as estradiol, estradiol hemihydrate and estradiol valerate in a patch, gel, cream, spray or oral capsule are categorized in the UK as: ultra low, low, medium, and high doses are shown (courtesy of BMS).

The advice is to commence on the lowest dose possible ie ‘ultra low” or “low”. For the shortest duration of time for relief of symptoms and paired with a progestagen (see Progesterone Therapy for Perimeopause & Menopause blog).

Patch, gel, cream or spray are the most favoured application, as absorbed transdermally.

The low and moderate doses show they work well for hot flushes, night sweats, and osteoporosis prevention. With osteoporosis prevention the ultra low dose is sufficient.

As written in the paper - Menopausal hormone therapy in the prevention and treatment of osteoporosis “Women who seek MHT for menopausal symptoms in their late 40s or early 50s will have the additional benefit of a reduced risk of bone loss and fracture . In such women, a separate first-line drug for prevention or treatment of osteoporosis is usually not required with estrogen (estradiol) doses equivalent to or higher than 25 mcg/day of transdermal or 0.5 mg/day oral. Lower doses of transdermal estradiol (14 mcg) have also been shown to have skeletal benefits”.

It is also really key to understand that there is no recommendation of HRT for the prevention of cardiovascular disease, dementia, or for increasing longevity.

Perimenopause and menopause oestrogen levels

After menopause, oestrogen levels drop dramatically, as there are few follicles in your ovaries producing it. Additionally, these follicles are no longer growing and producing the oestradiol spikes that occur during the menstrual cycle . The laboratory oestradiol levels of postmenopausal women are generally less than 73 pmol/L, a natural state of being.

Interestingly in the KEEPS study, an estradiol level of 162 pmol/L was associated with an almost complete resolution of hot flushes, and this is the dose that would approximately come from a 50 mcg patch. Another study looking at oral estradiol found that a 183 pmol/L estradiol level (achieved with a 1 mg oral dose- such as BIJUVE 1mg/100mg Capsules, with progesterone) also significantly improved hot flashes.

If we associate this back to our mentsruating years cycle flow, Oestrogen levels of 162- 185pmol/L are to expected in the early part of the menstrual cycle, so it makes sense that a 50 mcg estradiol patch or 1 mg of oral oestradiol works really well for hot flashes, and even lower doses of estradiol have been shown to protect the bones from osteoporosis as discussed previously.

More on bones and serum levels of oestradiol

Historically, the postmenopausal serum oestradiol reference range was considered to be <120pmol/L. However, as quantification methods have improved(using GC or LC tandem mass spectrometry assays) the true reference range has been demonstrated to be lower, likely less than 40 pmol/L

Similarly, previous investigators reported that the serum oestradiol level necessary to prevent or delay bone loss was 146-220pmol/L. However, as with the postmenopausal reference range, re-evaluating this range with improved quantification methods(LC tandem mass spectrometry assays) with increased sensitivity will likely demonstrate that the lower bound of the range can be decreased below 146 pmol/L

Given the downward shift in the postmenopausal serum oestradiol range with improved quantification methods, it could be safely assumed that the range necessary to prevent or delay bone loss may be shifted by the same amount. This would place the lower end of the range at 73pmol/L, which is two times the upper limit of the postmenopausal range <40 pmol/L. The key here is to check that your lab is using LC tandem mass spectrometry assays/ sometimes termed ultra sensitive oestradiol.

What is the starting dose of HRT

The standard starting dose of oestradiol is between a 25 mcg-50 mcg estradiol patch or equivalent(see chart).

As discussed previously, If a woman enters surgical menopause or has POI at age < 42 and had regular cycles before (meaning they weren’t in the late stage perimenopause), starting with a 100 mcg patch is suitable and then reduce the dose around age 50-51.

Many women, myself included, start on the very low doses of oestradiol. They may not work as well for hot flushes, but they still help some and are enough to protect bones, not improve bone loss, but prevent further deteriotaion ( which is why I personally began HRT) .

Oestrogen must be paired with a progestagen , and the dose and duration of a progestogen depends on the oestrogen dose. Please read my blog post Progesterone Therapy for Perimenopause & Menopause.

My personal thoughts, using the words of Lara Briden on my recent podcast, I‘d consider “a sprinkling or dusting“ (of transdermal O) + micronized Progesterone for the shortest time possible to reduce hot flushes, improve sleep and prevent bone loss. The greater the length of time elapsed into menopause, the lower and thus more stable our oestrogen levels - is a time for the body to settle into its natural state of being without the need for any replacement.

Brands | Delivery & Doses

*This is a chart I have collated of formulas available in the UK for reference, it is not intended for medical use but for information only.

HTML Table Generator

Oestrogens	Brands	Delivery	Doses
estradiol	Oestrogel Everol	Gel Patch	0.75mg per pump
estradiol valerate	Progynova	Tablet	0.5mg\| 1.0mg\|1.5-2mg
estradiol valerate + progestin as Medroxyprogesterone acetate	Indivina	Tablet
estradiol hemihydrate	Zumenon Estelle Solo Sandrena Lenzetto Estradot Estraderm FemSeven mono Progynova TS Estring	Tablet Tablet Gel Spray PATCHES “ “ “ “ Vaginal ring	1mg\| 2mg 1mg \| 2mg 0.75mg 1 pump 1.53 mg per spray 25mcg \| 37.5mcg \|50mcg\| 75mcg 100mcg 7.5 mcg/24 hours
estradiol hemihydrate + Progestins as; -Dydrogesterone(dyd) -Norethisterone(nor) -Medroxyprogesterone acetate(mpa) -Drospirenone(dro)	Kliofem (nor) Elleste Duet(nor) Indivina (mpa) Femoston(dyd) Novofem (nor) Trisequens(nor) Angeliq (dro) Evorel conti &seqi(nor)	Tablets Tablets Tablets Tablets Tablets Tablets Patch	Varying doses
estradiol hemihydrate + Progesterone	Bijuve	Capsules	1mg estradiol 100mg progesterone
Estriol	Ovestin	Vaginal cream
CEE	Premarin	Tablet	0.3mg \|0.625mg \| 1.25mg
Progestagens as either 1. Progesterone 2. Progestin	Brand	Delivery	Hormonal Activity AE- antioestrogenic AND- androgenic AA-antiandrogenic AM-antimineralcorticoid GLU=glucocorticoid EST- oestrogenic
Progesterone	Utrogestan	Capsules	AE\|AA\|AM
Progesterone + estradiol hemihydrate	Bijuve	Capsules	AE\|AA\|AM
Levonorgestrel	Mirena Combined patches FemSeven conti	IUD Patch	AE\|AND\|
Norethisterone	Combined patches Evorel conti & Sequi Combined tablets Kliovance Kliofem Novofem Trisequens Estelle Duet	Patch Tablets Tablets Tablets Tablets	AE\|EST\|EST\|
Dydrogesterone	Femeston range Duphaston	Tablets Tablets	AE\| weak AM
Medroxyprogesterone acetate	Combined tablets Indivina Solo Provera	Tablets Tablets	AE\| weak AND\|GLU
Drospirenone	Combined tablets Angeliq		AE\|AA

HRT and Oestrogen