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      • Viagra for IVF: How does it Work and Who Does it Benefit?

      Dr. Geoffrey Sher Recommends

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      In 1999, SIRM garnered quite a bit of media attention for our part in the birth of the world’s first “Viagra baby.” For those of you who aren’t familiar with the use of Viagra in IVF treatment, let me give some background…

      In 1989, we published a study that examined the correlation between the thickness of a woman’s uterine lining (the endometrium), and the successful implantation of embryos in IVF patients. Our study revealed that when the uterine lining was 9mm or thicker by the day of the “hCG trigger” shot, pregnancy and birth rates were substantially higher. While the success rate is much lower when the endometrial thickness is between 8 and 9mm, pregnancies and live births can and do occur. However when the endometrium measures less than 8mm the chance of a baby is very low indeed.

      A “poor” endometrial lining (under 9mm) is usually the result of the innermost layer of the uterine lining (basal/germinal endometrium) from which the functional (top) layer develops, not being able to generate proper development of the inner 2/3 (the functional endometrium). The functional layer is where the embryo implants. It is also the layer that sheds with menstruation in the event no pregnancy occurs.

      The main causes of a “poor” uterine lining are:

      1. Damage to the basal endometrium as a result of:

      a. Inflammation of the endometrium (endometritis) most commonly resulting from infected products left over following abortion, miscarriage or birth

      b. Surgical trauma due to over-zealous traumatic uterine scraping, (i.e. D & Cs)

      2. Insensitivity of the basal endometrium to estrogen due to:

      a. Over-use/misuse of clomiphene citrate

      b. Prenatal exposure to diethylstilbestrol (DES). This is a drug that was given to pregnant women in the 1960’s to help prevent miscarriage

      c. Over-exposure of the uterine lining to ovarian male hormones (mainly testosterone). Older women, women with diminished ovarian reserve (poor responders) and high responders (e.g., women with polycystic ovarian syndrome -PCOS) all tend to have raised LH production. Their ovaries tend to overproduce testosterone in response to LH when high doses of LH-containing gonadotropins are administered (e.g. Menopur) and when ovarian stimulation is undertaken using “microflare” protocols.

      3. Reduced blood flow to the basal endometrium as in cases of:

      a. Multiple uterine fibroids – especially when these are present under the endometrium (submucosal)

      b. Adenomyosis (excessive, abnormal invasion of the uterine muscle by endometrial glands).

      The Viagra Connection

      Because of the correlation between a thicker endometrium and successful embryo implantation, we tried various techniques to help IVF patients with thin linings prior to embryo transfer. Unfortunately, techniques such as supplementary estrogen therapy, aspirin administration and/or administration of high dosage gonadotropin fertility drugs all yielded disappointing results.

      In the latter part of the 90’s we began to recognize that it was possible to improve endometrial development in women who had “poor uterine linings” through the daily application of nitroglycerine skin patches during ovarian stimulation with gonadotropins. We believed this therapeutic effect to be attributable to the local action of nitric oxide (NO) causing improved endometrial blood flow and enhanced delivery of estrogen to the basal endometrium.

      About 70% of our IVF patients with compromised uterine linings treated with nitroglycerine skin patches, showed marked improvement in estrogen-induced endometrial growth and many went on to achieve viable pregnancies. Unfortunately, many women experienced unpleasant side effect such as severe headaches, palpitations, sweating, nausea and vomiting during the first few days of treatment. It was about this time that a drug called sildenafil (brand named Viagra) was gaining notoriety for treating erectile dysfunction. The mechanism of action for Viagra was the increase of penile blood flow through nitric oxide activity. Furthermore, it worked without the bothersome side effects of nitroglycerine. This prompted us to investigate whether this drug could replace nitroglycerine for the improvement of endometrial development.

      We soon observed that when administered vaginally, Viagra improved uterine blood flow significantly, but NOT when taken orally. We enlisted the services of a compound pharmacist to produce vaginal Viagra suppositories and began testing the effect of vaginally administered Viagra on uterine blood flow and on estrogen-induced endometrial development. Four women with chronic histories of poor endometrial development and failure to conceive following several advanced fertility treatments were evaluated for a period of 4-6 weeks and then underwent IVF with concomitant Viagra therapy. Viagra suppositories were administered four times daily for 8-11 days and were discontinued 5-7 days prior to embryo transfer in all cases.

      Our findings clearly demonstrated that vaginal Viagra produced a rapid and profound improvement in uterine blood flow and that was followed by enhanced endometrial development in all four cases. While three of the four women subsequently conceived, the study was too small to prove explicitly that these pregnancies could be attributed to the Viagra therapy.

      In October 2002, we were the first to report on the administration of vaginal Viagra to 105 women with repeated IVF failure due to persistently thin endometrial linings. All of the women had experienced at least two (2) prior IVF failures attributed to intractably thin uterine linings. About 70% of these women responded to treatment with Viagra suppositories with a marked improvement in endometrial thickness. 45% of these achieved live births following a single cycle of IVF treatment with Viagra. 9% miscarried. None of the women who had failed to show an improvement in endometrial thickness following Viagra treatment achieved viable pregnancies.

      Since the introduction of this form of treatment, more than 500 women have been reported treated and many have gone on to have babies after repeated prior IVF failure.

      It is important to recognize that Viagra does NOT work in all cases. In fact, about one third of women treated fail to show any improvement. This is because in certain cases, the basal endometrium has been permanently damaged and left unresponsive to estrogen (i.e. in cases of severe endometrial scarring due to inflammation, trauma or surgery).

      To be effective, Viagra must be administered vaginally. It is NOT effective when taken orally. We prescribe 20mg vaginal suppositories to be inserted four times per day. Treatment is commenced soon after menstruation ceases and is continued until the day of the “hCG trigger.” While ideally the treatment should be sustained throughout the first half of the cycle, most women will respond within 48-72 hours. For this reason, Viagra can be used to “rescue” a poor lining after the cycle has already started, provided that there is enough time remaining prior to ovulation, egg retrieval or progesterone administration.

      Following vaginal administration, Viagra is rapidly absorbed and quickly reaches the uterine blood system in high concentrations. Thereupon it dilutes out as it is absorbed into the systemic circulation. This probably explains why treatment is virtually devoid of systemic side effects.

      Recently, we began incorporating the use of Terbutaline (Brethine) at a dosage of 5mg orally three times daily, along with the vaginal Viagra. Viagra relaxes the muscle wall of uterine blood vessels while Terbutaline (a beta 2 adrenergic agent) relaxes the uterine musculature. Together they work to improve uterine blood flow beyond that which can be achieved through the use of either alone.

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      11 Responses to “Viagra for IVF: How does it Work and Who Does it Benefit?”

      1. Jill says:
        July 9, 2009 at 7:03 am

        Hi Dr. Sher – I am 33 years old. Started when I was 31. 1st cycle of femara resulted in abnormal pg. Since then have done another cycle of femara and 3 cycles of follistim/iui with no positive results at all.

        My lining has been an issue from the start – only once (for like a day or two) did it get above a 6, and usually hovers from 4-6. I have none of the reasons you describe here for thin lining. (I was on a medication called domperidome for gastroparesis for years, and after I went off the pill and did not get my period I realized this caused high prolactin levels which may have messed up my system for good, I don't know – but my doctor says at this point after being off the med for a year and a half, it shouldn't be the problem.) I had a normal endometrial function test at Yale. I've taken so much estrogen and had extremely high levels and still thin lining.

        I have sent your post to my RE (who I believe mentioned Viagra once but said it hadn't been proven to work) and am curious to see what he says.

        My question to you is – would you do IVF on a patient whose lining can't get above a 6? Is it worth a try (and all that money) or statistically unlikely to work and then a waste of effort and money?

        I also have just learned that my AMH levels are low (my clinic just started using this test for ovarian reserve) even though my fsh has always been good and I produce multiple follicles (13 this past failed cycle). My cycles are 35 days long without medication…So I am what my RE's office calls a difficult case with special issues….

        Thanks very much,
        Jill

        Reply
      2. Geoffrey Sher, MD says:
        July 9, 2009 at 12:25 pm

        In my opinion it is not advisable to do IVF with a lining of <8.0mm. The chance of success is very low and if you do conceive, implantation issues could greatly increase the risk of miscarriage ,placental insufficiency and intrauterine growth retardation. Might I suggest that you and I talk.

        I might be able to help shed some light here.To do so I would need a lot more information, so might I suggest that youarange a free consultaion with me by going to the home page of the SIRM website at http://www.haveababy.com home page and registering there online.

        Geoff Sher

        Reply
      3. Igloochic says:
        September 21, 2009 at 1:45 pm

        Dr. Sher,

        I'll find out for sure in a couple of days, but I'm fairly certain that my second IVF is going to be a failure. The first was fresh with a lining of 6.4. The second was FET with a lining of 7.7.

        I am 46 years old (using donor eggs). The embryo's are top quality. With the first fresh transfer I did get pregnant with twins most likely (just due to HCG levels and how fast they were rising) and lost them at 5 weeks 2 days. There is nothing "wrong" with me aside from the lining issue (all tests have been completed). With IUI I was able to get to an 8 lining by taking estrace vaginally beginning at 2 daily early in the cycle and advancing to three at the end of the cycle. With BCP and then lupron, I seem to have issues getting anywhere near 8 (and I'd prefer to see it higher).

        I asked about viagra therapy and the doctor's nurse dismissed it as unproven, but at this point, with only one more IVF in my future (I have to give up at some point) I'm wondering if my last effort should include viagra and perhaps the secondary drug Terbuteline? Would it be likely to make a difference? And does it matter if the transfer is frozen or fresh with these therapies?

        I have 16 top quality embryo's on ice now but there is no way I'm going through 8 more cycles (2 implanted each time). I don't know if they could be transfered if the therapy might work for me or if I should push harder for this through my existing office….

        Is this therapy of value to us old gals? :)

        Reply
      4. Geoffrey Sher, MD says:
        March 8, 2010 at 10:55 pm

        Whether Viagra will help depends very much on the reason for a thin lining. If it is due to previous inection of the uterine lining (endometritis) it often will not work. Sometimes using a suboptimal protocol of ovarian stimulation will render the endometrium less responsive to estrogen in that cycle. FET's traditionally give the best chance of a good lining because you avert some of the negative influences of a poor stimulation protocol thereby.

        Geoff Sher

        Reply
      5. הקוף הזה הוא אני says:
        April 29, 2010 at 10:26 am

        Hi,
        I am 27 years old with a poor endometrium.
        What are the chances to get a good reaction on a 3mm endometrium on a natural protocol and 5mm endometrium on a protocol with Estrogen and etc?
        Are there many prescriptions to have this vaginal Viagra or it's the same around the glob? (Can i have it from my own doctor?)

        Reply
      6. SaraECorgs says:
        November 3, 2010 at 1:50 pm

        Dr. Sher,

        I have had one fresh et in which a pregnancy was achieved, but I suffered from miscarriage at 9 weeks. Since that time, I have had 3 fets, all with negative results. This last time, my physician recommended the viagra protocol because my endometrial lining always hovered around .7. I did so with optimism, but the lining did not react, and remained at what we have started to refer to as "the usual". Is there anything that can be done, aside from pumping myself full of estrace (3 mg vaginally per day, along with 4 Estradot patches)? What tests can be performed to determine my lining's poor performance?

        Reply
      7. Cathrine says:
        November 21, 2012 at 9:42 pm

        Dear Dr Sher,

        I live in Sweden and here the pharmacies do not sell Viagra suppositories. Do you know if any European countries market these?

        Reply
      8. LindaRW says:
        February 12, 2013 at 2:33 pm

        Dear Dr. Sher,
        Thanks for giving us an opportunity to ask questions about this particular issue. My doctor is not available this week, and my FET cycle was cancelled yesterday, so this resource is great.
        I am a 39 yo woman, TTC for 3 years. I no longer have my left Fallopian due to an ectopic in 2004. Ive now had 4 ARTattempts (2 fresh IVF, 2 FET). Each time lining was perfect, or at least within the parameters. I’ve just had the 4th cycle cancelled because of thin lining. I think we were all a bit surprised. I was taking 1.0 lupron daily for 2 weeks then .5 lupron daily, 4vivelle patches every other day, and estrace vaginally 2x per day. My doctor never mentioned Viagra suppositories. I’ve only learned of it via Internet. Are there some patients for whom you would NOT recommend Viagra suppositories and why not? Also, in your opinion, once a woman has thin lining, is it then too thin forever or can it “bounce back”? Thank you

        Reply
        • Geoffrey Sher says:
          February 12, 2013 at 4:30 pm

          There are so may causes of a thin lining. Viagra will not help when the endometrium has been destroyed by post-pregnancy endometritis . Go elsewhere on this blog ( http://www.IVFauthority.com .On the home page, look for a “search bar” in the upper right hand corner. Type in “Endometrial thickness and Viagra therapy” This will take you to the relevant article. Also go to “Asherman’s syndrome”

          Consider calling 800-780-7437 or 702-699-7437 to arrange a telephone or Skype consultation (free of charge to those who reside in the United States or Canada) with me so we can discuss your case in detail.. While an audiovisual (Skype) interaction is much more personable and preferable than a discussion by telephone, either will suffice.

          Geoff Sher

          Reply
      9. BEATRICE says:
        March 22, 2013 at 1:40 am

        Dear Dr. Sher,

        I’ve been suggested by my Gyne doc to use Cialis to help endometrial growth (presently at max 6 mm) for the next week on 29/03 embryi transfer from frozen embryons.

        He told me to continue the Cialis 20 mg (1 x day vaginally) from now and up to the Hcg blood control that will occour 15 days after the transfer.

        Is it correct that I need to take Cialis for a so long time??? I heard of experiences of Viagra for istance up to the transfer, up to 2 days after it but not for such a long time.

        Thanks for your reply.

        Best Regards.

        Reply

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      My IVF Cycle Failed – What Went Wrong? Question #13: Did the Number of Embryos I Had Transferred Play a Role?
      This is the 13th in a series of answers to common questions about failed IVF. Virtually everyone recognizes that pregnancy with multiples (especially triplets or greater) is associated with a high incidence of premature delivery that has serious cons... more
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      My IVF Cycle Failed – What Went Wrong? Question #12: Might the Timing of Embryo Transfer – Day 2-3 (Cleaved) vs. Day 5-6 (Blastocyst) Play a Role?
      This is the 12th in a series of answers to common questions about failed IVF. (Note: I’ll be hosting a live video chat on Aug. 2 on the topic of Failed IVF where I’ll discuss the issues addressed in this series of posts and take your ques... more
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