In 1989, Dr. Sher first published a study that examined the correlation between the thickness of a woman’s uterine lining (the endometrium), and the odds of embryo implantation in IVF patients. This study revealed that when the uterine lining measured at least 9mm in thickness by the day of the “hCG trigger” (in fresh IVF cycles), or at the time of initiating progesterone therapy (in embryo recipient cycles, e.g. frozen embryo transfers-FET, egg donation-IVF etc.) , pregnancy and birth rates were substantially improved. An ideal estrogen-promoted endometrial lining should ideally measure at least 9mm in thickness and that an endometrial lining measuring 8-9mm is “intermediate”. An estrogenic lining of <8mm is in most cases unfavorable for implantation although not totally preclusive.
A “poor” uterine lining is usually the result of the innermost layer of endometrium (the basal or germinal endometrium from which endometrium grows) being unable 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 at least 2/3 of the full endometrial thickness and is the layer that sheds with menstruation.
The main causes of a “poor” uterine lining include and the damage to the basal endometrium as a result of:
- Inflammation of the endometrium (endometritis), often chronic and subclinical, that arises usually from uterine or vaginal instrumentation or more severely from products left over following abortion, miscarriage or birth.
- Surgical trauma due to traumatic uterine scraping, (i.e. due to an over-aggressive D
Insensitivity of the basal endometrium to estrogen due to:
- Prolonged, over-use/misuse of clomiphene citrate
- Prenatal exposure to diethylstilbestrol (DES). This is a drug that was given to pregnant women in the 1960’s 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 includes the following:
- 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”
More than 20 years ago, after reporting on the benefit of vaginal Sildenafil (Viagra) to women who had implantation dysfunction due to thin endometrial linings, Dr. Sher was proud to announce the birth of the world’s first “Viagra baby.” Since the introduction of this form of treatment, many women with thin uterine linings who have been thus treated have gone on to have babies after repeated prior IVF failure.
For those of you who aren’t familiar with the use of Viagra in IVF, allow us to provide some context. It was in the 90’s that Sildenafil (brand named Viagra) started gaining popularity as a treatment for erectile dysfunction. The mechanism by which it acts is through increasing blood flow through increasing nitric oxide activity. This prompted an investigation 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. Forty five percent (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 probably explains why treatment is virtually devoid of systemic side effects.
It is important to recognize that Viagra will NOT be effective in improving endometrial thickness in all cases. In fact, about 30%-40% 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) and following extensive surgical injury to the basal endometrium (as sometimes occurs following over-zealous D&C’s). Therefore it is important to identify those patients ahead of time who are likely to be helped by this technique.
(On a side note, Viagra is heavily in the news today. In addition to its beneficial effects on erectile dysfunction and endometrial thickness, it has recently been shown to dramatically decrease the incidence of Alzheimer’s in men who have used it for their erectile dysfunction. Therefore its vasodilatory effects seem to affect multiple organs in a positive fashion.)