About seventeen years ago, after reporting on the benefit of vaginal Sildenafil (Viagra) for women who had implantation dysfunction due to thin endometrial linings, I was proud to announce the birth of the world’s first “Viagra baby.” For those of you who aren’t familiar with the use of Viagra in IVF, allow me to provide some context.
It was as far back as 1989 when I first published a study that examined the correlation between the thickness of a woman’s uterine lining (the endometrium), and the subsequent successful implantation of embryos in IVF patients. This study revealed that when the uterine lining measured <8mm in thickness by the day of “hcg trigger” (in fresh ivf cycles), or at time initiating progesterone therapy embryo recipient cycles, e.g. frozen transfers, egg donation-ivf etc.), pregnancy and birth rates were substantially improved. currently, it is my opinion, that an ideal estrogen-promoted endometrial lining should ideally measure least 9mm measuring 8-9mm “intermediate”. estrogenic <8mm most cases unlikely to yield a viable pregnancy.A “poor” uterine lining is usually the result of the innermost layer of endometrium (the basal or germinal endometrium from which endometrium grows) not being able to respond to estrogen by propagating an outer, “functional,” layer thick enough to support optimal embryo implantation and development of a healthy placenta (placentation). The “functional” layer ultimately comprises 2/3 of the full endometrial thickness and is the layer that sheds with menstruation in the event that no pregnancy occurs.The main causes of a “poor” uterine lining are:
- Damage to the basal endometrium as a result of either
- Inflammation of the endometrium (endometritis) most commonly resulting from infected products left over following abortion, miscarriage or birth
- Surgical trauma due to traumatic uterine scraping, (i.e. due to an over-aggressive D & C)
- Insensitivity of the basal endometrium to estrogen due to either
- Prolonged, overuse/misuse of clomiphene citrate
- Prenatal exposure to diethylstilbestrol (DES). This drug was given to pregnant women in the 1960s to help prevent miscarriage
- Over-exposure of the uterine lining to ovarian male hormones (mainly testosterone): Older women, women with diminished ovarian reserve (poor responders) and women with polycystic ovarian syndrome -PCOS tend to have raised LH biological activity.. This causes the connective tissue in the ovary (stroma/theca) to overproduce testosterone. The effect can be further exaggerated when certain methods for ovarian stimulation such as agonist (Lupron/Buserelin) “flare” protocols and high dosages of menotropins such as Menopur are used in such cases.
- Reduced blood flow to the basal endometrium:
- Examples include:
- Multiple uterine fibroids – especially when these are present under the endometrium (submucosal)
- Uterine adenomyosis (excessive, abnormal invasion of the uterine muscle by endometrial glands).
“The Viagra Connection” Treatments such as supplementary estrogen therapy, aspirin administration and/or administration of high dosage gonadotropin fertility drugs, aimed at improving endometrial development have all yielded disappointing results. It was in the 90s that Sildenafil (brand named Viagra) was gaining popularity as a treatment for erectile dysfunction. The mechanism by which it acted was through increasing penile blood flow through increasing nitric oxide activity. This prompted me to investigate whether Viagra administered vaginally, might similarly improve uterine blood flow and in the process cause more estrogen to be delivered to the basal endometrium and thereby increase endometrial thickening. We found that when Viagra was administered vaginally it did just that! However oral administration was without any significant benefit in this regard. We enlisted the services of a compound pharmacy to produce vaginal Viagra suppositories. Initially, four (4) 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. Three (3) of the four women subsequently conceived. I expanded the trial in 2002 and became 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% achieved live births following a single cycle of IVF treatment with Viagra The miscarriage rate was 9%. None of the women who had failed to show an improvement in endometrial thickness following Viagra treatment achieved viable pregnancies.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 phenomenon probably explains why treatment is virtually devoid of systemic side effects Since the introduction of this form of treatment, thousands of women with thin uterine linings have been reported to be treated, and many have gone on to have babies after repeated prior IVF failure. It is important to recognize that Viagra will NOT be effective in improving endometrial thickness in all cases. In fact, about one third of women treated fail to show any improvement. This is because in certain cases of thin uterine linings, the basal endometrium will have been permanently damaged and left unresponsive to estrogen. This happens in cases of severe endometrial damage due mainly to post-pregnancy endometritis (inflammation), chronic granulomatous inflammation due to uterine tuberculosis (hardly ever seen in the United States) or following extensive surgical injury to the basal endometrium (as sometimes occurs following over-zealous D&C’s). 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.