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

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.