Viagra and the Endometrial Lining by Geoffrey Sher, M.D

In normal and "stimulated" cycles, pre-ovulatory endometrial thickness and ultrasound appearance, is predictive of potential embryo (pregnancy) potential following In Vitro Fertilization/Embryo Transfer (IVF/ET). It has been shown that with "conventional" IVF/ET (where the woman receives fertility drugs and has her own fresh embryos transferred to her uterus), optimum implantation potential requires that on the day of the hCG trigger the endometrium should measure more than 9.0mm and ideally (although less important than thickness) should have a "triple line appearance".

While some viable pregnancies may occur with a lining of 8-9mm, very few will occur when the endometrium measures less than 8mm. For some reason that remains unclear at present, this rule of thumb might apply to third party embryo Recipients (Ovum donation, IVF-Surrogacy) and to women undergoing Frozen Embryo Transfers (FET) (i.e., where the recipient receives estrogen and not gonadotropins, to prepare the uterine lining). Here, a lining measuring more than 8mm on the day that progesterone supplementation is started, may be adequate.

A "poor" endometrial lining more commonly occurs when the basal ("germinal" endometrium, from which the full endometrial layer develops is compromised in its response to estrogen). This most commonly occurs when:

1. The basal endometrium is permanently damaged:

a) Inflammation of the uterine lining (endometrium), i.e., endometritis occurring following a septic delivery, abortion or miscarriage,

b) Following repeated or over-aggressive D&C procedures,

c) Following uterine surgery that causes excessive endometrial scarring.

2. Endometrial resistance to estrogen:

a) Overuse of clomiphene citrate

b) Developmental, as sometimes occurs following prenatal in-utero exposure to diethylstilbestrol (DES).

3. Reduced blood flow to the basal endometrium

a) Multiple uterine fibroids (especially when present immediately under the endometrium (submucosal).

b) Following extensive uterine surgery

c) Adenomyosis. ( http://www.inciid.org/article.php?cat=glossary&id=53 )

4. Over-exposure to ovarian testosterone

Overgrowth of ovarian stroma (stromal hyperplasia) that produces testosterone in response to luteinizing Hormone (LH). This occurs more commonly in older women (beyond 40 years); in poor responders to gonadotropins (especially when they are given large amounts of LH-containing gonadotropins (e.g. Repronex, Menopur); and in very high responders to gonadotropin stimulation (e.g women with polycystic Ovarian syndrome (PCOS).

Over-exposure of endometrial cells to increased testosterone production (as might occur in all such cases (especially when high doses of LH-containing gonadotropins are administered), reduces endometrial receptivity to estrogen. This might explain why, when the same women ultimately resort to ovum donation or undergo FET's where no ovarian stimulation with gonadotropins is undertaken, the subsequently thickens normally following treatment with estrogen.

TREATMENT OF A "POOR ENDOMETRIAL LINING WITH VIAGRA VAGINAL SUPPOSITORIES"

Attempts to augment endometrial growth in women with poor endometrial linings by bolstering circulating estrogen blood levels (through the administration of increased doses of fertility drugs, aspirin administration and by supplementary estrogen therapy) yielded disappointing results.

In 1995/96, the Sher Institutes for Reproductive Medicine 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. It was believed this therapeutic effect to be attributable to the local action of nitric oxide (NO) so produced, causing improved endometrial blood flow and enhanced delivery of estrogen to the basal endometrium.

About 70% of SIRM 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.

Accordingly, when Sildenafil (Viagra) which also increased tissue nitric oxide activity was introduced and was shown to facilitate penile erection by increasing penile blood flow, without eliciting bothersome side effects, we decided to investigate whether this drug could replace nitroglycerine for the improvement of endometrial development.

We elected to incorporate Viagra into in an attempt to improve local uterine absorption and minimize the incidence of systemic side effects. We soon observed that when administered vaginally it improved uterine blood flow significantly, but NOT so, 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 vaginal 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 this was followed by enhanced endometrial development in all four cases. While three of the four women subsequently conceived, the study is too small to prove that these pregnancies can be attributed to the Viagra therapy. Larger independent and controlled studies will be needed to demonstrate this.

In October 2002, SIRM reported 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 and 45% achieved live IVF- births following a single cycle of treatment with Viagra. 9% miscarried.

None of the women who had failed to achieve an improvement in endometrial thickness following Viagra subsequently and underwent embryo transfers in the same cycle during which Viagra was administered, 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 Vaginal Viagra does NOT work in all cases. In fact about 1/3 of women so treated will fail to show any improvement. This is because with certain causes of a "poor endometrium", the basal endometrium has been permanently damaged and left unresponsive to estrogen (e.g. severe endometrial scarring due to inflammation, trauma or surgery).

Viagra is administered in the form of 20mg vaginal suppositories inserted four times per day. Treatment is commenced soon after menstruation ceases and is continued until the day of the hCG trigger (when used with ovarian stimulation), the day of the LH surge (in natural cycles) or, until the commencement of progesterone in "embryo recipient cycles" (ovum donation, FET's, gestational surrogacy and embryo adoption).

While ideally the treatment should be sustained throughout the first half of the cycle, most women will respond within 48-72 hours, such that Viagra can be used to "rescue" a poor lining provided that there is enough time remaining prior to ovulation, egg retrieval or progesterone administration.

Viagra is NOT effective when given orally for these purposes. Following vaginal administration Viagra immediately reaches the uterine blood system in high concentrations and then as it is absorbed into the systemic circulation it dilutes out. This probably explains why treatment is virtually devoid of systemic side effects.

Our first patient to achieve a live birth following Viagra treatment had experienced numerous IVF failures. She has since gone on to have her second Viagra baby and now has a boy and a girl both born at full term and healthy.

Source: http://www.inciid.org/printpage.php?cat=infertility101&id=315

Category: Hormones, IVF, research