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[Hurdity]

Hi there

I wrote to Besins about this  a few weeks ago because the subject of the 3-day break on 100 mg utrogestan used as continuous combined regime keeps coming up. I have previously posted studies about the effectiveness of vaginal progesterone and specifically utrogestan in protecting the endometrium but not about the rationale behind and studies into the 3 day break in detail.

I got a reply from Besins in early March but haven't got around to posting it but thought members might be interested. I haven't looked at or followed up any of the refs and some may be research we already know about.

Here is their response verbatim:

Utrogestan® (progesterone) 100 mg Capsules – Rationale of the day 1-25 regimen
As you may be aware the UK Summary of Product Characteristics (SPC) for Utrogestran 100
mg Capsules1 states:

“The recommended dose is 200 mg daily at bedtime, for twelve days in the last half of each
therapeutic cycle (beginning on Day 15 of the cycle and ending on Day 26). Withdrawal
bleeding may occur in the following week.

“Alternatively 100 mg can be given at bedtime from Day 1 to Day 25 of each therapeutic
cycle, withdrawal bleeding being less with this treatment schedule.”

It is possible that licences differ for different countries and therefore the SPCs also differ.
Please refer to the UK SPC1 (available at www.medicines.org.uk/emc/) for local prescribing
information.

Only the doses stated in the SPC1 can be recommended and therefore included in the
prescribing information. Use of doses above 200 mg daily would be considered off-licence
and would remain the responsibly of the prescribing healthcare professional.

Finally, you asked for clarification on why the day 1-25 continuous regimen stated in the
SPC1 includes a 3-day progesterone break. The following information identified from the
published literature may be of use to you.

Chronic unopposed endometrial exposure to oestrogen increases the risk for endometrial
hyperplasia or cancer in women with an intact uterus. The primary menopause-related
indication for progesterone use is to prevent endometrial overgrowth and the increased risk of
endometrial cancer during oestrogen therapy use.2, 3

A 3-day break in the cycle for Utrogestan 100 mg continuous regimen is mostly based on:

1. The effect of the progesterone on endothelium and vascular angiogenesis in the
endometrium.4

2. The suppression of endometrial oestrogen and progestin receptors with exogenous
progestins.5

A break in progesterone would aid in the oestrogen and progestin receptors being recovered
in the endometrium and significant reduction in episodes of breakthrough and unexplained
bleeding by stopping excessive angiogenesis induced by the continuous combined regimen.4-6

A continuous regimen of Utrogestan 100 mg/day is usually preferred by patients who do not
want withdrawal bleeding during the therapeutic cycles. Clinical trials have investigated the
anti-proliferative and amenorrhoea inducing effects of a low dose of micronised progesterone
(100 mg/day) when used in a continuous regimen of 25 days per cycle with oestradiol gel.7-9

These studies had employed the 3-day break from micronised progesterone in the continuous
regimen during the therapeutic cycle and has demonstrated the efficacy of the regimen in
protecting the endometrium and inducing amenorrhoea.

A low micronised progesterone dose (100 mg/day) over a long period (25 days per month)
demonstrated efficient control of the oestrogen-induced endometrial proliferation as
evidenced by histological examinations of the endometrium which showed the endometria
being slightly developed, without hyperplasia in all the 78 endometrial samples collected.

This endometrial response resulted in a high incidence of amenorrhea.7 A study by Foidart et
al8 investigated the anti-proliferative effect of 100 mg/day of oral micronised progesterone
administered simultaneously with 1.5 mg oestradiol for 25 days/month by mitotic activity and
deoxyribonucleic acid (DNA) synthesis, where DNA syntheses was reduced by 70% with
combined treatment. Amenorrhoea was induced in all patients with bleeding episodes
occurring for less than 0.25% of the duration of treatment.8 Gillet et al9 demonstrated that a
low dose of oral micronised progesterone (100 mg/day) given for 25 days/calendar month
was able to fully control endometrial proliferation induced by an adequate dose of
percutaneous oestradiol, by efficiently inhibiting mitoses in endometrial glands. This study
also showed that the use of a low dose of progesterone allows maintenance of a low incidence
in spotting and a very frequent amenorrhoea. Of the 98 patients included in the treatment
regimen, amenorrhoea occurred in 93.3% and 91.6% of the patients after 3 and 6 months of
the treatment respectively.9

References:

1. Utrogestan 100 mg Capsules SPC (July 2017)
2. Furness S et al, Hormone therapy in postmenopausal women and risk of endometrial
hyperplasia. Cochrane Database Syst Rev. 2012; (:CD000402.
3. Sjögren LL et al, Hormone replacement therapy and the risk of endometrial cancer: a
systematic review. Maturitas 2016; 91:25-35.
4. Vazquez F et al, Progesterone Regulates Proliferation of Endothelial Cells. The Journal of
Biological Chemistry. 1999; 274(4): 2185-2192.
5. Casper RF, Regulation of Estrogen/Progestogen Receptors in the Endometrium. Int J
Ferti. 1996; 41(1):16-21.
6. Moyer DL et al, Prevention of endometrial hyperplasia by progesterone during long-term
estradiol replacement: influence of bleeding pattern and secretory changes. Fertil Steril.
1993; 59:992–7.
7. Philippe E et al, The endometrium under the effects of hormone replacement therapy in
menopause with percutaneous estradiol and low-dose micronized progesterone.
Pathologica. 1993; 85(1099):475-87.
8. Foidart JM et al, Endometrial tolerance of long-term combined hormone replacement
therapy: analysis of the cell cycle. Horemone Replacement Therapy: Standardized or
Individually Adapted Doses? The proceedings of a special symposium held at the 7th
International Congress on the Menopause, Stockholm, Pantheon Publishing. 1993.
9. Gillet JY et al, Induction of amenorrhea during hormone replacement therapy: optimal
micronized progesterone dose. A multicenter study. Maturitas 19. 1994; 103-115.

Well - there you have it!

Apologies I haven't got time to reformat it as it was a pdf document but hope it is interesting and helpful to some of you! I'm right busy at the moment but wanted to get this out there! Don't know where the smiley came from but maybe the code for it is embedded in the text (like when you type 3 question marks!!!).

Happy reading

Hurdity x

[pepperminty]

Hi Hurdity,

very interesting, - I wonder what they would classify as an adequate dose?  "  by an adequate dose of
percutaneous oestradiol, by efficiently inhibiting mitoses in endometrial glands."


PMX

[Hurdity]

I've looked up that paper (the abstract) and it referes to 1.5 mg estradiol so that is two pumps - ie the standard medium dose. I presume adequate for symptoms and oesteoporosis protection? It is an odd word to use - ie vague, when science is about precision! Maybe the full paper elucidates further!

Hurdity x

[Tc]

Thanks for this hurdity.
Am I right in taking from this that they are saying 25 days is optimal for controlling the thickening effects of E but that the 3 day break is beneficial regarding receptors being recovered and for other reasons.

I realy dont get why I have been told to take it continuously without the 3 day break. I dont understand where that thinking comes from as it seems of no particular extra "protective" benefit than 25 days and doesnt follow the reasoning in these guidelines for having  a 3 day break.
It seems to be prescribing a way to take the med outwith the guidelines and research.and I wonder what my docs  basis/evidence is  for doing this.

if it is because my gynae is absolutely horrified by the idea of post meno bleeding then that seems unfounded too as this article states bleeding is minimal on 25 days/3 day break regime.
 I'm wondering if when us ladies on "continous" talk about it whether  we are all actually talking about the same thing.  It would seem Continous includes the 3 day break, whereas the continous iin my case is no break.

Has  anyone else who is on it continuously been told not to take the 3 day break?
I'd be interested to hear.
The resulting build up in progesterone after months on it without a break has become intolerable for me.

[CLKD]

   brought back memories of typing 'calls for papers' on specific formats, usually 500 words which had to be sent off by a certain date, then the Abstracts and Paper that was to be presented ........ initially on up-right type-writers with tip-ex  ...........

'adequate' probably means that they haven't actually talked to sufferers   

[meno lesley]

Hi

I take utrogestan 100mg continuously and see Nick Panay who prescribed it. I found I had a bleed stopping it for 3 days.

Lesley

[Tc]

Thanks lesleyx

[Dotty]

I take Utrogestan continuously with no problems. The research I read says that it's easier to remember to take it every day and taking it every day reduces the risk of breakthrough bleeding x

[Hurdity]

There is later research showing that taken every day with medium doses of oestrogen it keeps the endometrium thin. This is why most prescribe it like this. Tc was asking about the rationale behind the 3 day break and I was posting the response from Besins. Presumably they have not re-evaluated this in the light of later research - which may not have been so detailed re structural aspects of the endometrium?

However I would suggest that if you bleed on the 3 day break - then you should. Surely this means that the lining has thickened enough to shed and might carry on thickening if used continuously? Presumably menolesley this hasn't happened to you (either breakthrough bleeding or thickened lining so it must work OK?)?

Tc if you are getting side effects from continuous use then these won't diminish much with taking prog 25 days out of 28 and you will also have to contend with the withdrawal too. Far better to take it properly cyclically if you can but you need to get your doc on side!

Hurdity x

[Tc]

Thanks hurdity. My thinking is the same. I'm on 3rd day of withdrawal now and today has not been good to say the least If I'm going to suffer withdrawal then a 3 day break seems pointless.
I think I need to let it clear from my system and start again with a cycle. . Which to be fair was advice you and other ladies gave me a while ago.but all the time I  had my gynae in my ear scaring me and encouraging me to stick with it.

Thank you for taking the time to reply. It realy seems to have been the topic of the day. I think the fact we are all told by our docs that utrogestan is the most body identical doesnt help. My gynae seems to think it Is,  and I quote  " the best tollerated".  but I dont know where she gets that evidence from. Maybe those of us who struggle with it are in the minority but how are we to know that. Many ladies on here have problems with it which todays  posts have shown  but there may be countless ladies not on here who have given  up on it or not realised it was causing their issues.
It's also very clear that there is confusion from docs when prescribing it .
This forum realy brings these issues to light
.

[pepperminty]

It is such a shame that you can't get dydrogesterone seperately as that would be another option . I wonder how one would go about protesting to the pharma company that makes it? Surely as they produce it anyway in Femeston then producing a seperate tablet wouldn't be difficult! They seem to be reducing options at the moment.


Peppermintyx

[meno lesley]

Hi Hurdity

I haven't had any breakthrough bleeding taking it continuously and have had scans to check lining and has always been thin.  I have tried lots of different hrts over the years and really struggled but have found Elleste Solo and Utrogestan the best for me. I must admit it's not perfect as do have side effects but cope better on this regime.

Lesley

[Hurdity]

Bump for sheila99

Re your comment on the other thread sheila - this might help re utrogestan dosing?

Hurdity x