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.

233 Comments

Nne

Hi Dr, i am taking Progesterone Vaginally 2 tablets 3X daily and Estrogen tablets 2 times daily, i started spotting ( only seeing blood when i wipe sometimes) i have done an Ultrasound and i am now at 7 weeks and 2days with the heartbeat visible and it was a spontaneous pregnancy after egg retrieval while waiting for a FET. is anything wrong or would this just be irritation from the progesterone? i am so worried and theres no ultrasound till the 6th of october

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Dr. Geoffrey Sher

That is interesting and lucky! I wish you well.

Indeed, it is very possible that the spotting is due to local irritation. In the absence of US evidence of intrauterine bleeding, a vaginal speculum examination should be able to detect the local origin!

Good luck!

Geoff Sher

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Laura

Hi Dr, I always read your answers, and I would really appreciate your comment in my case. We did a 5 day blast transfer (2) in a natural cycle, only adding progesterone Just in case. As I had a low initial hcg of 14, we stopped the medication. I had a bleeding 4 days after (I assumed menses), but 5 days after the 14 value, I had a beta of 53, that kept rising as follows…

August 30th 5day transfer
Sept 8th 14 Progesterone 15
Sept 13th 53 Progesterone 1.1 (because stop P 4 days ago?)
Sept 17th 119 Progesterone 4.3
Sept 20th 243 Progesterone 5 6
Sept 23th 473 Progesterone 6.7

What do you think?

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Laura

Thank you so much for answering! Last Quick question, would you be too concern about the possibility of being ectopic with that rising pattern? Or basically not viable? Thank you very very much!

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Dr. Geoffrey Sher

Probably not but it could be an ectopic. Your Re will likely be keeping an eye on this!

Geoff Sher

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Luz

Hi! I found your article so informative, thank you.
I had IVF and transferred 3 frozen 5day blast on Sep 14th. I did not have any HCG shot and I am testing positive on a hpt. I’m taking 3 times a day estradiol 2mg and 300 mg progesterone morning and night with 200 mg progesterone afternoon. Is this too much? I’m supper bloated

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Kate

I am pregnant after using gonal-f and IUI, my initial labs at 11dpo showed a beta hcg of 16 and estradiol level of 28, I have been put on an estrogen supplement and at 13dpo showed a beta of 39 and estradiol of 82. I have read low estradiol is causes from low quality embryos? Is this true? Should I be writing this pregnancy off or continuing with supplemental estradiol.

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Dr. Geoffrey Sher

You should repeat the hCG test in 2 days. The level should be around 80. If not it could be pointing to an implantation failure.

Good luck!

Geoff Sher

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Rebecca

Is spotting common after stopping progesterone & estrogen at 10 weeks? Should I be concerned?

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Dr. Geoffrey Sher

It is not common but can occur without a significant underlying problem.. Visit your doctor for an ultrasound examination.

Geoff Sher

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Betsy

I’m on 2 patches of estrogen since transfer. At the time my Estradiol was 443 and progesterone over 40 Im so happy that on 9dpt5dt, my Beta came back at 113. However my estradiol dropped to 235 and progesterone stayed the same at over 40. The nurse did not seem concerned and said anything over 200 is good. Is this drop normal and should I request to increase the number of patches?

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Dr. Geoffrey Sher

I would not be overly concerned…but please discuss with your RE!

Good luck!

Geoff Sher

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Mila Drell

Dr.

I am on the 5th week of pregnancy right now and I missed one estradiol pill two days ago. Since then, I am taking everything on time. Please let me know if it could possibly effect the embryo/pregnancy?

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Lulu

Hi Dr. Sher,
I am on day 3 after a frozen egg/5 day embryo transfer. I have been taking estradiol for two weeks and then a week ago 4 mg estradiol a day with 1 mg of progesterone shot and 2 suppositories. Since the beginning, I have been having heavy brain fog/heaviness in the brain. Is this a common side effect? Should I ask to lesson the dosage?

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Anne

Hello,
I am 5 weeks pregnant after a fresh transfer and my clinic did not send me home with enough estrogen pills. My doctor here in the US said that she will not prescribe more. Should I find a new doctor or just hope for the best? Thanks.

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Dr. Geoffrey Sher

If you conceived after a fresh transfer with prior gonadotropin stimulation, you probably do not need more hormonal stimulation….But discuss with your RE before making any changes!

Geoff Sher

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Michele

I am 6w4d. My doctor is having me stop estrogen at 7w. He says it’s not necessary anymore. Do you agree or should I push to continue reading it until week 10?

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Dr. Geoffrey Sher

While I prefer continuing to 10w, the decision on what to do is between you and your treating RE.

Geoff Sher

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Megan

In frozen embryo transfer, I can see why you need to take estrogen/progesterone until 10 weeks, but my question is whether there is a chance that you could be taking too much estrogen/progesterone and casue negative feedback/down regulation of placental estrogen/progesterone production? Ie do we need to wean/titrate down on the estrogen/progesterone around 8-10weeks to allow placenta to take over, or does the placenta produce these hormones regardless of exogenous supplementation?

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Dr. Geoffrey Sher

The placenta produces these hormones regardless of supplementation.

Geoff Sher

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Melanie Diedrick

Hello Dr S! Do you titrate or stop the progesterone and estrogen suddenly at 10 weeks?

Thanks

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Emily Weitzel

Hello,
I am 9w5d pregnant with twins. I had 2 fresh embryos transferred on day 5. No prior fertility problems, my husband just had a vasectomy. I have since been on 2/ml progesterone injections every three days, and 3 100mg suppositories in between. I am also on 6mg of estrogen daily.
Is there any benefit to continuing these prescriptions, or is there any risk to the fetuses if I stop?
Was there any reason for me to be on them to begin with?

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Dr. Geoffrey Sher

I advise all my patients to stop hormonal supplementation at 10 weeks!

Good luck!

Geoff Sher

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Elle

Hello Dr. Sher,
I had a 3 day FET on 3/17. I had my beta testing done on 3/29 – 297, 3/31 – 602 and on 4/2 – 1563. On 4/13 I had my first ultrasound. The baby was measuring 6weeks 1day and had a heartbeat of 115. My doctor tested my progesterone and it came back 8.9 which is extremely low. I am on 1ml PIO daily. My doctor thinks there was an error with the testing and is having me go to another testing facility today. She said that for some doing IM PIO injections progesterone levels are usually between 30-50. What do you prefer progesterone levels to be at at this stage? Thank you so much for your input! Elle

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Dr. Geoffrey Sher

I agree with your RE. P4 of >10ng/ml is OK … but preferably >20ng/ml.

Good luck!

Geoff Sher

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Taki

I had day 5 frozen embryo transfer. On day 12 HCG was 87. Day 15 my HCG was 107. I was on progesterone I.M injections and estrogen pate he’s. My doctor think the rise of HCG is very low and not safe to continue with this pregnancy. My progesterone and estrogen are stopped. I have blood tests again on day 17. Estrogen and progesterone levels are normal. In your opinion do u think this pregnancy can still be viable?

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Dr. Geoffrey Sher

Sadly, it is not likely to be a viable pregnancy!

Sorry!!

Geoff Sher

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Vivian

I doctor I soon to stop estradiol pills and progesterone oil injection. What should I do or eat to help baby growing? Thanks

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Allyssa

Hi Dr. Sher, I did a FET on 03/05. 3dp5dt my blood was drawn and met doctor indicated my estrogen was super low I was previously on 2 patches. Lining was 10mm at time of transfer. They increased me to 3 patches and they added estradiol pills 2mg 1x daily. Should I be preparing for a failed FET?

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Lucia Cantero

Dr. Sher,

I had unprotected sex during ovulation and will be going into luteal phase stimulation for egg retrieval next ovulation this month, a mere few days, after this ovulation. Will the chance of a possible pregnancy be affected by this early stimulation? Do reproductive embryologist have ways to see if an egg is fertilized before implantation produces higher hCG? What would you do in this case. What are the chances and ways menopur and clomid can affect an already existent pregnancy?

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Dr. Geoffrey Sher

To me, this would no be an issue, since I am vehemently against Luteal Phase stimulations. They do NOT yield comparable results, in my opinion! AND yes, if you ovulated, the stimulation would likely disrupt the chance of a pregnancy!

Good luck!

Geoff Sher
PH: 702-533-2691

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