Progesterone-Estrogen Hormonal Supplementation in IVF: How Does it Work and What is its Value?

Ovulation occurs within 38-42 hours of initiation of the spontaneous luteinizing hormone (LH) surge (which can be detected in the blood or urine prior to this event) and/or hCG administered following controlled ovarian stimulation (COS) with gonadotropins.

One or more eggs are released with spontaneous or induced ovulation. Those follicles that ovulate and many of those emptied at egg retrieval, then undergo “luteinization”, converting to one or more a yellow bodies or corpora lutea (CL) that produces both progesterone and estrogen. The greater the original number of mature follicles, the greater the progesterone/estrogen production is likely to be. Accordingly, women on fertility drugs have higher luteal phase progesterone/estrogen levels.

The effect of the pre-ovulatory hCG injection is usually sustained for 1-2 weeks exerting a protracted influence on ovarian progesterone/estrogen production. A few days later, provided that embryo implantation takes place, the early trophoblast (root system of the conceptus) begins to produce its own progesterone/estrogen as well as hCG, in ever increasing amounts. By the 8th week of pregnancy the early placenta provides for all hormonal needs of the developing conceptus. There is compelling evidence to show that hCG augments ovarian (corpus luteum) progesterone release while also promoting growth and development of the trophoblastic “root system” of the conceptus (which eventually will develop into the placenta) as well as estrogen and progesterone production. Since, at the same time, hCG probably also promotes the production of more hCG, it might be considered to be a self-propagating hormone.

By the 8th-9th week of pregnancy, the trophoblast has replaced the ovaries as the dominant source of progesterone and estrogen production. Thereafter there is probably little or no benefit in supplementation with progesterone/estrogen It follows that a low blood progesterone blood level is much more likely to be the consequence rather than the cause of a failing pregnancy. Thus in such cases the administration of progesterone/estrogen in an attempt rescue a failing pregnancy is tantamount to “shutting the gate after the horse has left the stable.”

An obvious situation where progesterone/estrogen supplementation is required is in cases where the woman is an embryo recipient (i.e., ovum donation, embryo adoption, gestational surrogacy and frozen embryo transfers-FET).

By the 8th to 10th week of pregnancy, conversion from reliance upon the corpus luteum to sustain the pregnancy has occurred and further fetal development, supported by the hormonal production of the placental trophoblast. Thus thee is in my opinion little or no benefit in estrogen/progesterone supplementation beyond the 10th week.

While progesterone /estrogen supplementation likely has benefit in cycles involving pituitary down-regulation with GnRH agonists (e.g. Lupron, Buserelin, Superfact, Decapeptyl) or antagonist (Ganirelix, Orgalutron, Cetrotide) where luteal phase hormonal deficiency is more prevalent, there is no conclusive evidence that patients undergoing gonadotropin stimulation without the use of a GnRH agonist or an antagonist would derive benefit from such hormonal supplementation.

Hormonal supplementation usually involves the daily intramuscular administration of progesterone +/-  vaginal suppositories (comprising estradiol and micronized progesterone) until a blood pregnancy test is performed approximately eight days later (the chemical diagnosis of pregnancy). If the pregnancy test is negative or the plasma hCG levels fails to rise appropriately in the ensuing days, such hormonal support is discontinued. For those that cannot tolerate daily intramuscular progesterone, Crinone or Endometrin vaginal applications can be used instead.

37 Comments

Elle

Hello Dr. Sher,
I’m 41 and had a FET on 7/8 with a 4AA PGS blastocyst that had fully hatched after thawing. Went in for my beta on 7/17 hcg was 143, then again on 7/15 hcg was 417. I was then handed off to my OB. I went in on 8/2 for my first ultrasound at which I was 6wks 2 days. The baby measured exactly at 6wks 2 days and had a heartbeat of 119. The doc tested my estrogen and progesterone levels – they came back this morning as estrogen = 343 and progesterone = 18.5. My question is do you feel that my progesterone level is high enough? I’m currently on 1ml PIO nightly. I’ve read on certain sites that over 25 is ideal. Also, he started me on a baby aspirin – what are your thoughts about taking that as well? Thank you SO much for your help & guidance!! Elle

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Fab

My doctor has increased my dsily progynova frm 8mg daily to 12mg after embryo transfer 3 weeks ago. I had beta hcg done 2 weeks after transfer positiv 745 and on 3rd week today 4800. Is it safe for me and the fetus, to be takin tat dose of progynova? Doctor may keep it until week 10. My lining was 9.3mm the day before transfer. Also taking 75mg aspirin, 60mg duphaston and crinone twice a dah.

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Dr. Geoffrey Sher

I am not sure why this increase?. However it should not adversely affect the conceptus or the pregnancy…in my opinion.

Geoff Sher

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Izabela Kaczynska

Dear Doctor Sher,

I am two and a half weeks after FET. The pregnancy have been confirmed and I am waiting for my 8 week scan. I am on high doses of Progynova tablets (10mg a day) and 400mg Cyclogest pessaries twice a day and I was told to continue with this dosage. The infertility comes from male factor and I have never had any issues with building of the lining. I asked for a blood test to check my hormones levels because I was worried that the dose is to high but my clinic says it’s a standard protocol.
Does too much estrogen can affect in any way the development of the fetus?

Thank you,
Izabela

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Dr. Geoffrey Sher

I do not think there is anything for you to be concerned about at this point!

Geoff Sher

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Izabela Kaczynska

Dear Dr. Sher
Thank you very much for your comment. It put my mind at ease.
Izabela

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Tera

I am currently in my 8th week of pregnancy from an FET. I’m on 800mg of progesterone (prometrium) and 8mg of estrace daily. The last two weeks I’ve had a problem with thrombosis in a hemangioma in my hand. It’s very painful, swollen and a little scary. I’ve read estrogen can agitate this. Is it safe to cut back my estrogen dose at this time to 4mg daily?

Thanks for any information.

Dr. Geoffrey Sher

Hi Tara,,

From my personal point of view, you could lower the dosage of estradiol but that decision is one that needs to be discussed with your personal treating physician.

Geoff Sher

MZ

Hello, in your experience have you seen any cases of estrogen induced pancreatitis in ivf patients? I am 3 days post transfer and my pregnancy test is not for another few days. My upper left abdomen has been hurting constantly. Also how many weeks after a positive pregnancy test does the estrogen intake usually continue?

Dr. Geoffrey Sher

I could be wrong but I am not aware of a link to pancreatitis.

Geoff Sher

Ange

Hi Dr Sher
Can you please clarify, when you say “8th week of pregnancy” do you mean gestational age, fetal age, or weeks after ET?
Thanks for the very helpful article!

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Dr. Geoffrey Sher

No,it refers to 8 weeks following the last menstrual period…

Geoff Sher

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Sharon

Dr. Sher.

Thank you for the helpful information!

It appears that different fertility centers stop Estrace/Progesterone at different time points. Is there any harm in taking Estrace/Progesterone past 10 weeks gestation? Do you typically stop Estrace/Progesterone at the same time or sequentially (for example stopping Estrace at 8 weeks and Progesterone at 10 weeks).

Thank you

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Dr. Geoffrey Sher

I do not believe there is a need to go beyond 10 weeks, but doing so should not be harmful…in my opinion.

Geoff Sher

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Angela Mcgee

What is your preference? Oral estradiol vs intravaginal vs Delestrogen injections? And Why?

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Dr. Geoffrey Sher

Oral estrogen is first absorbed via the gastrontestinal system into the portal blood system to reach the liver. and from there it passes via the liver before reaching the systemic circulation and the uterus. In the process it is altered. This is avoided when vaginal or parenteral (injections) are used. Vaginal absorbtion is somewhat erratic. Parenteral estrogen (injections) estradiol valerate (Delestrogen) is the best way to go because absorption can be controlled allowing the estrogen to directly access the systemic circulation and thereby reach the uterus, unaltered. Furthermore, a significant amount of oral estradiol or Estrace (the oral estrogen compound used most commonly) converts to estrone before reaching the uterus and this is this is far less beneficial than estradiol.

Geoff Sher
Geoff Sher

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Dr. Geoffrey Sher

I do not prescribe Estrace. discuss with your personal RE please!

Geoff sher

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Resh

Hello doc.
I had done fet blastocyst on 22nd jan and underwent blood test yesterday. The readings of prog is 25 and e2 is 615. Pls advise if this reading is good enough. I am 41 years old and this is my 2nd ivf cycle. Had 5 good blastocyst which they have inserted 2 of yhem in this cycle.

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Dr. Geoffrey Sher

I would need to know the hCG level rather than E2 and progesterone to tell if you are implanting and likely to be pregnant.

Geoff Sher

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Resh

Thanks for ur revertal. The doc has asked me to do bhcg on 5th feb. I am sure tat will show the actual results. I was quiet surprised why this blood test was done wen it doesnt give an idea of positive or negitve results. Wl revert bak as soon as i hv my reports. Tks n hv a great day ahed.

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Jamie

This was a great article Dr. Sher. Many thanks! I love the level of detail you use. It’s really helpful.

I have been looking and looking, but I can’t find an answer to this question so maybe you can enlighten me. I am 31 years old with no known issues (our infertility is male factor). We are gearing up for our first frozen cycle and my doctor has me on Estrace and Progesterone (vaginally) for 7 days until the end of my cycle, then I after stopping those I should get my period. Then I’ll call in my Day 1 and we’ll start prepping for a FET that cycle. My question is…why am I on anything at all this cycle when technically we’re taking a “break” between our egg retrieval (which was in December) and our FET (which will be in February). What is the purpose of taking both these meds if we’re not doing anything this month? Please help….this feels like such a technical question but I can’t find an answer!

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Jamie

I should add that originally we were going to head straight into a FET in January so they had me take Estrogen starting on my Day 1. But we changed out minds around about Day 8 and said that we would prefer to have a month off. Could having started Estrace on Day 1 be the reason they feel we must keep up the protocol this month, even if we’re not having a FET until the following month? (Thought I’d provide that info in case it’s relevant.)

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Dr. Geoffrey Sher

As I see it the likely reason is to be able to launch and precisely time the treatment for your FET.

Geoff Sher

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Grace

Hi Dr. Sher,
I just recently finished my first ivf cycle, to find out this afternoon that I am having a chemical pregnancy. I was taking 1 cc of PIO and 4 mg of Estrace. At 5 days past transfer, I went in to my dr for with bright red spotting, and when they ran my blood, they found that my progesterone levels were extremely low (20). This comes after my levels were in the thousands after my retrieval. My Dr upped me to 1.5 PIO, 3 days later my levels had raised a bit, bit the dr still has no idea why my body isn’t absorbing the PIO. He’s sure that this is the reason my pregnancy failed. I have heard of people getting PIO and suppositories, is this something that you would recommend? Any idea why my levels will not rise even with daily injections?

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Dr. Geoffrey Sher

In my opinion, a low progesterone is the consequence (rather than the cause) of a failing implantation.

Geoff Sher

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Deborah

Dear Dr. Sher, I am almost 48 and preparing for my first ever FET using a 6 day BB blastocyst (PGD tested). I made the blast at age 44. This last year my cycles went from 27-28 days the first half of the year to most cycles now at 25 days, with a few 26, 27 or 29 days thrown in. I would rather not do a Lupron cycle. What would you recommend in my case? This is my last chance. Thanks

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Dr. Geoffrey Sher

I personally would advise against natural cycle FET at your age. You need to use hormone therapy coming off a BCP in my opinion…whether you use Lupron overlap (which I believe to be preferable) or not.

Frozen Embryo Transfer (FET): A frozen embryo transfer cycle is initiated by administering an oral contraceptive (OC) to the recipient. This is later overlapped with Lupron daily for 5-6 days. The OC is then withdrawn, but the daily Lupron injections are continued until the onset of menstruation. Next, the Lupron dosage is reduced and intramuscular (IM) estradiol valerate (Delestrogen) is administered every 3 days. The objective of the estradiol is to achieve and sustain an optimal plasma E2 concentration of 500pg/ml-1000pg/ml and a 9mm endometrial lining as assessed by ultrasound examination. Intramuscular and/or intravaginal progesterone is administered daily starting about 6 days prior to the FET and continued along with twice weekly IM Delestrogen until the 10th week of pregnancy or until it has been confirmed that the patient is not pregnant.
Daily oral dexamethasone commences with the Lupron start and continues until a negative pregnancy test or until the completion of the 8th week of pregnancy. Then it is tapered down and discontinued. The recipient also receives prophylactic oral antibiotics starting with the initiation of Progesterone therapy, until the day after ET. Usually we would thaw vitrified blastocysts with the objective of having 1, 2 or 3 for transfer; depending on a couple’s stated preference. Commencing on the day following the ET, the patient inserts a vaginal progesterone suppository daily and this is continued until the completion of the 8th week of pregnancy or until a negative pregnancy test.
As an alternative regimen for women who cannot tolerate intramuscular Progesterone (PIO), we prescribe either Crinone vaginal gel or Endometrin vaginal inserts according to protocol. If you’d like to explore one of these options, talk to your physician. For blastocyst FET’s, the blood pregnancy tests are performed 13 days and 15 days after the first progesterone administration is commenced.

Good luck!

Geoff Sher

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Mark

In your opinion is it necessary to monitor progesterone levels after the 10th week mark with a normal ultrasound? How can one be certain that the placenta is producing the necessary amount to sustain the pregnancy?

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