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[Hurdity]

Hi there - this subject keeps coming up and newer members won't have seen all the threads where these studies have been quoted so I'm doing a separate post as I can't always find the old threads!

Vaginal progesterone in menopause: Crinone® 4% in cyclical and constant combined regimens  2000

D.de Ziegler124, R.Ferriani3 , L.A.M.Moraes3 , and C.Bulletti4

Human Reproduction, Vol. 15, (Suppl. 1), pp. 149-158, 2000

https://humrep.oxfordjournals.org/content/15/suppl_1/149.full.pdf

Compliance with hormone replacement therapy (HRT) is notoriously low despite ample documentation of clinical efficacy. The two major reasons given by women who discontinue HRT are uterine bleeding and side-effects. The recent development of a controlled and sustained vaginal progesterone gel allowed single daily application and made prolonged use such as for menopause possible. Here we report our clinical experience with two therapeutic options for HRT using natural progesterone administered vaginally. A first group of 69 menopausal women received the sustained release vaginal progesterone gel, Crinone® 4% (45 mg daily) from days 1-10 of each calendar month with oestrogens taken continuously. A second group of 67 women received Crinone 4% twice weekly in conjunction with continuous oestrogen therapy. Endometrial thickness was evaluated before and after 6 months of treatment. Histological verification was obtained in all cases of abnormal bleeding. At 6 months, 63 out of 69 (91.9%) women receiving progesterone cyclically experienced predictable withdrawal bleeding. The vast majority, 54 (80.6%) of 67 women receiving Crinone in constant combined association with oestrogen therapy, remained amenorrhoeic throughout 6 months of therapy. AH cases of abnormal bleeding were biopsied and no hyperplasia was seen. Our results indicate that both regimens using the sustained release vaginal progesterone gel controlled bleeding in HRT. Combined with the lower incidence of side-effects characteristic of vaginal progesterone, both vaginal progesterone regimens have the potential of improving HRT compliance.

Efficacy of oral micronized progesterone when applied via vaginal route.2004

Choavaratana R1, Manoch D.
http://www.ncbi.nlm.nih.gov/pubmed/15222511

Abstract
The aim of the study was to compare the efficacy of oral micronized progesterone when applied by the vaginal route. The comparative study of serum progesterone levels between oral and vaginal micronized progesterone administration was conducted in sixty female volunteers. The subjects were equally divided into two groups to receive the drug either via the oral or vaginal route. The subjects' profiles showed that there was no significant difference in general characteristics between these two groups. The blood tests for estrogen and progesterone levels were performed on all volunteers before and after the drug administration. The data collected from the experiment revealed that the serum progesterone levels achieved by oral administration (5.06 +/- 2.95 ng/ml) differed significantly (p < 0.001) from those achieved by vaginal administration (8.26 +/- 4.09 ng/ml). The data also revealed that the serum progesterone levels of the oral administration group (4.23 +/- 2.68 ng/ml) did not differ significantly (p = 0.925) from the other group (4.15 +/- 3.40 ng/ml) when the serum estrogen level was less than 30 pg/ml. On the contrary, when the serum estrogen level was at least 30 pg/ml, there was a significant (p < 0.005) difference in the serum progesterone levels between these two groups (6.32 +/- 2.99 ng/ml for the oral route and 9.76 +/- 3.23 ng/ml for the vaginal route).

Endometrial effects, bleeding control, and compliance with a new postmenopausal hormone therapy regimen based on transdermal estradiol gel and every-other-day vaginal progesterone in capsules: a 3-year pilot study
Cicinelli et al 2005

http://apps.elsevier.es/watermark/ctl_servlet?_f=10&pident_articulo=90010354&pident_usuario=0&pcontactid=&pident_revista=605&ty=58&accion=L&origen=zonadelectura&web=www.elsevier.es&lan=en&fichero=605v83n06a90010354pdf001.pdf

(The above link doesn't seem to work any more...so try this one below)

https://www.fertstert.org/article/S0015-0282(05)00403-6/fulltext

In a 3-year prospective study, 30 postmenopausal women received transdermal E2gel and every-other-day vaginal P in capsules. At study completion, endometrial thickness was significantly reduced as compared with baseline (2.7 0.5 vs. 3.4 0.9 mm), endometrial biopsy showed endometrial atrophy in all cases, and amenorrhea was achieved in 92.6% of cycles, while excellent patient satisfaction was achieved. (Fertil Steril 2005;83:1859–63. ©2005 by American Society for Reproductive Medicine.)

Transdermal estradiol and oral or vaginal natural progesterone: bleeding patterns.2010
Di Carlo C1, Tommaselli GA, Gargano V, Savoia F, Bifulco G, Nappi C.
http://www.ncbi.nlm.nih.gov/pubmed/20575654

Abstract
OBJECTIVE:
To evaluate the effects on bleeding pattern of two different doses of natural progesterone (NP) administered per os or per vagina in association with transdermal estradiol in a continuous, sequential estrogen-progestin therapy.
METHODS:
A prospective, randomized trial was conducted on 100 patients randomized into four groups. Each group received transdermal 17beta-estradiol treatment at the dose of 50 microg/day. Groups A and B received NP per os at the dose of 100 mg/day and 200 mg/day, respectively. Groups C and D received NP per vagina at the dose of 100 mg/day and 200 mg/day, respectively.

RESULTS:
After 12 cycles of treatment, no significant differences were observed in endometrial thickness between groups, suggesting that all treatments are effective in balancing the effects of estradiol on endometrium. Regarding bleeding control, patients in Groups C and D showed a higher number of episodes of regular bleeding than patients in Groups A and B and fewer episodes of spotting. The better control of bleeding was associated with a higher treatment compliance in patients who received vaginal NP, with a larger percentage of women completing the study.

CONCLUSION:
Transdermal estrogen replacement therapy combined with 100 mg of micronized NP administered per vagina from the 14th day to the 25th day of each 28-day cycle leads to good cycle control and provides excellent patient satisfaction without serious side-effects. This therapy could be a treatment of first choice in early postmenopausal patients.


Endometrial response to concurrent treatment with vaginal progesterone and transdermal estradiol. 2012
Fernández-Murga L1, Hermenegildo C, Tarín JJ, García-Pérez MÁ, Cano A.

http://www.ncbi.nlm.nih.gov/pubmed/22321028'


ABSTRACT Objective To describe the effect of the intermittent administration of vaginal progesterone and a low-dose estradiol patch on endometrial stability, as assessed by the rate of amenorrhea and endometrial stimulation. Methods This was an open study in which 64 moderately symptomatic, postmenopausal women were treated in the outpatient clinic of our University Hospital for different intervals up to 1 year. The treatment consisted of a combination of patches delivering 25 µg/day estradiol and intravaginal pills containing 100 mg of micronized progesterone. Patches and pills were administered concomitantly in a twice-a-week protocol. The endometrial response was assessed by endovaginal ultrasound completed with suction biopsy when required. Results Both cumulative amenorrhea and no-bleeding rates increased progressively and reached 88.9% and 100.0%, respectively, by the 12th month. Isolated or repetitive episodes of bleeding, bleeding and spotting, or only spotting were reported by three, four, and 12 women, respectively. Endometrial thickness remained unaltered. Endometrium was atrophic in the seven women in whom a biopsy was performed. Conclusion The substantially reduced progestogen load determined by this combination achieved an acceptable incidence of spotting or bleeding when associated with a low estrogenic dose. There was no apparent endometrial stimulation. Additional studies are required to confirm this observation.


E-mail from information manager at Ferring ( previous manufacturer of Utrogestan) 2011

"The product monograph talks of two trials of vaginal use as part of HRT – they're small patient populations – 20 and 30 patients in each.

One study used 100mg once daily vaginally for 21 days of 28 day cycle – the study lasted a year and was undertaken in 20 patients. Symptoms were significantly reduced, bone density remained and no adverse effects were seen. The endometrium was safely protected from the estrogenic effect of 1.5mg transdermal Oestrogel.


Another of 30 patients over 36 months studied the use of 100mg vaginal Utrogestan every other day. For most patients there was absence of bleeding and good patient satisfaction. There was a reduction in mean endometrial thickness and at the end of the study endometrial atrophy was seen in all cases. Five of the 30 women dropped out due to vaginal bleeding. (1.5 mg per day Sandrena gel)"  Cicinelli et al 2005

The references are:

Spritzer et al Exp Clin Endocrinol Diabetes 2003; 111 (5) 267-273

Vilodre et al Gynecol Endocrinol 2003; 17 (4) 323-328.

Endometrial Protection: Which Progestogen Is Best? 2015
By Jeffrey T. Jensen, MD, MPH Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland
March 1, 2015

https://www.ahcmedia.com/articles/134766-endometrial-protection-which-progestogen-is-best

Extract
“The commercially available 4% vaginal progesterone gel (Crinone®) has been evaluated for endometrial protection in combination with transdermal estradiol. This product delivers 45 mg/day, and no cases of endometrial proliferation were observed in a small study involving 35 subjects. However, this is not approved for HRT and is quite expensive.”
The impact of micronized progesterone on the endometrium: a systematic review.2018

P. Stute, L. Wildt & J. Neulen (2018)
Climacteric, 21:2, 111-122,
https://www.tandfonline.com/doi/full/10.1080/13697137.2017.1421925

Abstract
Postmenopausal women with an intact uterus using estrogen therapy should receive a progestogen for endometrial protection. International guidelines on menopausal hormone therapy (MHT) do not specify on progestogen type, dosage, route of application and duration of safe use. At the same time, the debate on bioidentical hormones including micronized progesterone increases. Based on a systematic literature review on micronized progesterone for endometrial protection, an international expert panel's recommendations on MHT containing micronized progesterone are as follows: (1) oral micronized progesterone provides endometrial protection if applied sequentially for 12-14 days/month at 200 mg/day for up to 5 years; (2) vaginal micronized progesterone may provide endometrial protection if applied sequentially for at least 10 days/month at 4% (45 mg/day) or every other day at 100 mg/day for up to 3-5 years (off-label use); (3) transdermal micronized progesterone does not provide endometrial protection.



That's it for now! I'm sure there are more recent ones too. Please post any later studies if you find them...

Also a reminder that Utrogestan is manufactured to be used vaginally or orally - here is the information I also posted recently on another thread:

"Utrogestan is manufactured to be taken orally or vaginally - it is only in the UK that it is only licensed for oral use as part of HRT (but the 200 mg capsules is now only licensed or rather marketed, for vaginal use for infertility).  You will see the database of medicines (the "base de donnees publique des medicaments") it is listed as: "UTROGESTAN 100 mg, capsule molle orale ou vaginale " - similarly for 200 mg. In the info it gives the indication for vaginal route, amongst other uses, if side effects are experienced with oral use:

"Dans toutes les autres indications de la progestérone, la voie vaginale représente une alternative à la voie orale en cas:

· d'effets secondaires dus à la progestérone (somnolence après absorption par voie orale)."

In all other indications of progesterone, the vaginal route respresents an alternative to the oral route in the case:
.. of  side effects due to the progesterone (sleepiness after absorption by the oral route).

http://base-donnees-publique.medicaments.gouv.fr/affichageDoc.php'specid=61673424&typedoc=R

Hope this helps

Hurdity x

[Turkish delight]

Cool thanks Hurdity!

Noticed this paper shows half the recommended dose of micronised progesterone vaginally compared to NICE guide of 200 mg orally.
See copy paste under here...

"CONCLUSION:
Transdermal estrogen replacement therapy combined with 100 mg of micronized NP administered per vagina from the 14th day to the 25th day of each 28-day cycle leads to good cycle control and provides excellent patient satisfaction without serious side-effects. This therapy could be a treatment of first choice in early postmenopausal patients."

Nice guidelines are for 200 mg orally and no mention of vaginally, I have that right don't I?

I feel good about this bcz I'm on 100 mg vaginally for 14 days for 1 pump Oestrogel.

Incidentally, and unconnectedly I got my repeat of Oestrogel as Oestrodose, the label had a sticky pharmacy detailed label over one side of the box with "Oestrogel" written on it and all the details for that. I used it and have noticed no difference in any way, just one day a tad more of an alcohol whiff but that wasn't any cause for concern. Thought you'd be glad to hear this after the constant debate re differences.

TD

[Wrensong]

Thanks for taking the time to post this, Hurdity.  Makes for interesting & reassuring reading & great to have it all together.  Will be helpful to many members, I'm sure.

[Beaker]

Thanks Hurdity - this answered a few questions I was about to ask 

[Karen P]

Thank you so much, this is really helpful info, and has put my mind to rest.

Karen x

[Sheanie]

Really useful information. Thank you! I am wondering if a table of some sort with all the results in would be a good idea.... I'm also wondering how I'll find the time to make one. Essential for that presentation though. I will post it if I make it. 

I'm on 2 pumps of Estrogel and was taking one 100mg Utrogestan orally every day, but after 3 months, I found it made me very drowsy. I'm on one 100mg Utrogestan vaginally every other day now. Feeling a lot better now. And this research evidence makes me feel reassured I'm safe doing that.

[Hurdity]

Sheanie....however it would be better to have a scan at some point to check whether this regime is suitable for you as an individual and be vigilant about any suspicious spotting or bleeding.

Hurdity x

[Hurdity]

Bump - for members asking about the safety of vaginal utrogestan on utrogestan/estrogel support group.

Also to re-emphasise (and re-post) my last point in the main post because the question comes up regularly and it seems that some health professionals and menopause "experts" are not aware of either the studies nor that utrogestan is actually manufactured (on the continent) to be taken via both routes - oral and vaginal.

Utrogestan is manufactured for oral or vaginal use

Utrogestan is manufactured to be taken orally or vaginally. It is only in the UK that it is only licensed for oral use as part of HRT - now using only the 100 mg capsules. The 200 mg capsule is now only licensed or rather marketed, for vaginal use for infertility but was formerly licensed (or rather packaged) for HRT. In other words the same capsules can be taken either way - by mouth or by vagina.

You will see the French database of medicines (the "base de donnees publique des medicaments") it is listed as: "UTROGESTAN 100 mg, capsule molle orale ou vaginale "  (soft oral or vaginal capsule) - similarly for 200 mg. In the info it gives the indication for vaginal route, amongst other uses, if side effects are experienced with oral use:

"Dans toutes les autres indications de la progestérone, la voie vaginale représente une alternative à la voie orale en cas:

• d'effets secondaires dus à la progestérone (somnolence après absorption par voie orale)."

Translation: In all other indications of progesterone, the vaginal route respresents an alternative to the oral route in the case:
.. of  side effects due to the progesterone (sleepiness after absorption by the oral route).

http://base-donnees-publique.medicaments.gouv.fr/affichageDoc.php'specid=61673424&typedoc=R


Hurdity x

[kayellvee]

Thanks, Hurdity and for your reply to me in the other thread.  I'll switch to vaginally and hope that it helps.

[Tc]

Thanks hurdity. So glad you bumped this as I missed it first time.

I've taken utrogestan for 2 cycles orally at 200. Mg.  Bleed day 8 each time.  Headache nausea and migraine throughout use.. I've just started 3rd cycle 200mg oral dose last night and already getting the side effects. It's obviously a pattern which is going to repeat.

So i want  to switch to use vaginally tonight  From reading this info 100mg is sufficient  if used vaginally for 12 days as it's more direct route to uterus. . But the info and trials all refer to  low dose eastrogen.use.  I am on 2x100 estradot patch. .  So I'm a bit wary about only using 100mg P . There doesnt seem to be a lot of information out there on how much P is needed to protect uterus during high dose eastrogen use. My GP seems to think its unchartered territory and cant offer any advice 

I could err on side of caution and use 200 vaginally but it doesnt seem anyone else uses it this way.  I 'm not sure if using too much vaginally might imbalance me the same way too much orally did  or whether I need to worry about atrophy of the lining 

Last bloods in June were 179pmol E.  But I dont know whether to go by this or to go by the fact I'm on such high E dose.

Thank you for taking the time to post and bump this thread. I'm sure it has and will answer a lot of questions for many ladies. I guess I'm in something of a minority using such a high dose of eastrogen.and I'm still unsure what to do for the best X

[Ladybt28]

Sorry if I haven't read this right - anyway - I use 200mg vaginally on a cycle Tc - not 100mg because I am on 4 pumps of gel which is considered on the high side although nowhere near as high as you. x

[Tc]

Thanks lady.
I didnt know of anyone else using 200 vaginally. So you've  answered my question.

Think I will use 200 to be safe side.

Xxxx

[Saffy]

Hi TC, just catching up! I use 2x100 Utro vaginally on a cycle and I'm on 2x100 Estradot twice a week but have used this dose of Utro vaginally since I started on the 25 Estradot patches  .

[Tc]

Hiya saffy. Aah yes. The 200 club. I'm back in after a brief foray into the 250 club. Thanks.  Do you use 7 or 12 days.    What is your bleed like Hope you don't mind me asking. But mine
is weird. Starts on day 8 of utrogestan and finishes on day 12.  So not on withdrawal as it's supposed to. 

How are you?

[Saffy]

I use 12 days (for my sins!) . My bleed is pretty textbook, starts 4 or 5 days after stopping the Utro and very light, much lighter than when I was having proper periods (and they were never particularly heavy, just horrifically painful). I only really have two days of proper bleeding and then it trails off with a bit of spotting for a couple of days (sometimes slightly longer). Slight cramping almost as soon as I stop the Utro and a bit more on the night before and first day of the bleed. The amount and pattern of bleeding hasn't changed since I was on the 25 patches, bizarrely.

I was having infrequent periods when I started the HRT, though I had just had a couple in quick succession, and I didn't bother to sync with a cycle as I just wanted to get started so I've just been lucky I guess (sound of slightly hysterical laughter...). It is strange that quite a few women seem to bleed consistently before they have completed the progesterone phase.

How am I? Who knows  . Libido has now fizzled out, I think my hair has started shedding again and I have a face full of spots (bleed due but I think they are worse due to the T)  . Still tired, occasionally a bit 'warm', probably a bit less exhausted than I was. Muddling along with 50/50 goodish days/meh days. I keep trying to convince myself that I'm better, and I am, and I hear how others are feeling on here and I'm grateful I am not in that place but really I'm nowhere near the person I was before peri began in earnest *sigh*.

God that was cheery . Oh and I am also the carrot person! xxx