Marissa (39y) and her husband, Pete (43y) presented with a history of having had 2 healthy children together. Marissa was a normally menstruating/ovulating lady with a fertile husband. The birth of her 2nd child was complicated by partial delivery of the placenta and was accompanied by a post-partum hemorrhage (bleeding). A manual removal of the retained piece of placenta was undertaken following which her uterus was deemed to be empty. After the birth of her baby, Marissa had a low-grade fever, lower abdominal pain, malaise and a malodorous lochia (post-delivery secretions) that persisted for >2 weeks. At this point an ultrasound was done and it revealed that there was still some retained placental tissue in her uterus, and a D & C was performed. In the years that followed, Marissa noticed a marked reduction in menstrual flow. However, since she was still ovulating normally (based upon home ovulation testing, she thought nothing of it and tried in-vain to have a 3rd child.
When 3 years of trying to have another baby proved unsuccessful, the couple sought the services of a fertility specialist who performed a hysteroscopy to examine Marissa’s uterine cavity. This established that Marissa had significant intrauterine adhesions that were in-part obliterating her uterine cavity. The adhesions (synechiae) were transected and cleared and a balloon catheter was temporarily placed inside her uterine cavity to try and avert refusion of the inner opposing uterine surfaces. A follow-up hysteroscopy done 3 months later established that a regular contour of Marissa’s uterine cavity had been restored.
At this point, Marissa and Pete elected to do IVF. She responded well to a modest stimulation with gonadotropins (fertility hormones) and underwent an egg retrieval where 14 mature eggs were harvested from her ovaries. At the time of egg retrieval, her uterine lining measured 6.5mm (“inadequate”). Fertilization by intracytoplasmic sperm injection (ICSI) followed by culture, resulted in 5 blastocysts, four of which were determined by preimplantation genetic testing (PGT) to be chromosomally normal (euploid). These were frozen for subsequent transfer to the uterus at a later date.
About 4 months later an attempt was made to prepare Marissa’s uterus for frozen embryo transfer FET). However, the endometrial lining was refractive to hormone therapy with oral estrogen and aspirin therapy, failing to thicken beyond 7mm (very “inadequate”). The cycle was appropriately canceled.
Subsequently, when several attempts at stimulating endometrial growth with high dosage estrogen by oral/vaginal/ skin patch and intramuscular administration failed to improve matters, Marissa sought a consultation with me as a “last resort” before either abandoning further attempts at having a baby or resorting to Gestational Surrogacy.
It was clear to me that incomplete evacuation of Marissa’s uterus after the birth of her last baby had been at the root of her problem. This almost certainly had resulted in endometritis which severely damaged her basal (germinal”) endometrium and caused an inflammatory process that fused the inner surfaces of her uterine cavity. Because of this, implantation could not take place.
Endometrial Thickness and implantation potential:
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 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. Currently, it is my opinion, that 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 unlikely to yield a viable pregnancy.
A “poor” (<8mm) 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:
- 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:
- 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:
- 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”
Eighteen years ago years ago, after reporting on the benefit of vaginal Sildenafil (Viagra) for to women who had implantation dysfunction due to thin endometrial linings I was proud to announce the birth of the world’s first “Viagra baby.” Since the introduction of this form of treatment, thousands of women with thin uterine linings have been reported treated and many 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 me 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 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. 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) such as was the case with Marissa.
While about 75% of women with thin uterine linings see a positive response to treatment within 2-3 days. The ones that do not respond well to this treatment are those who (like Marissa) have severely damaged inner (basal/germinal) endometrial linings, such that no improvement in uterine blood flow can coax an improved response. Such women usually require a Gestational Surrogate.
I performed a trial of Viagra therapy on Marissa, but alas, her uterine lining failed to improve sufficiently so I advised the couple to seek ot a Gestational Surrogate, which they are now considering.