About Femara/Letrozole Safety for Ovulation Induction

I'm just starting to research the safety of Femara/Letrozole but I'll continue to update this post as I find out more. This summary from the ASRM 2005 Conference was interesting:


Biljan (Montreal, Canada) and colleagues[7] reported the results of a study of the births of 150 babies following treatment with the aromatase inhibitor letrozole. In this study, 5 mg of letrozole was given in all cycles analyzed. Perinatal outcome information over 36,000 deliveries from the same hospital was used to provide the control population. Maternal age and the proportion of multifetal deliveries (110 singleton and 20 twins) were higher in the letrozole group. Malformations were detected in 4.7% of the newborns in the letrozole group and in only 1.8% of the newborns in the control population. When the type of malformation was considered, locomotor, bone and cardiac malformations were more common following letrozole treatment.

The findings of this study are surprising, as until now no adverse perinatal effects had been reported with aromatase inhibitors. They were considered to be safe because they are used in only the early follicular phase and their half-life is short. Some points about this report need to be raised, however. The rate of malformations in the control group is lower than that usually observed. Several factors influence the rate of malformations, such as maternal age, the order of the pregnancy, gestational age at delivery, medication use during pregnancy, and maternal medical complications. One must make an effort to control for these factors during the analysis. Maternal age was higher in the study group and there were more multiple gestations. It is also known that the incidence of congenital malformations is higher following infertility treatment, so it would be better to compare the letrozole group to groups undergoing other types of infertility treatment. Still, the findings of this study should lead to more careful use of aromatase inhibitors for infertility management. Further studies need to evaluate the association between aromatase inhibitors (various doses) and congenital malformations.

More about the Highlights of the ASRM 2005 Conference

The half-life of Letrozole is about 2 days. This means that it takes about 2 days for the concentration of the drug to drop in one-half in the serum. In general, a drug will be completely eliminated in 5 half-lives. In the case of Letrozole, this is about 10 days. The pharmacokinetic studies which determined the half-life of the drug may not have been done in women of reproductive age as the drug was to be used in post-menopausal women. Thus it may be metabolized differently in younger women. In fact, two unknown metabolites are mentioned in the PDR which may have untoward biological activity. Most studies used Letrozole until about day 7 of the cycle. Thus, it is possible that the drug could still be in the system at the time of conception around day 14 or so if we assume it takes 5 half-lives to be completely excreted and potential metabolites exist that could have biological activity. Also, the half-life of a drug may be increased by increasing the dose of the drug. Some use Letrozole at 5.0 mg or 7.5 mg doses, potentially increasing the half-life of the drug. The dose in breast cancer patients is 2.5 mg per day. There is more to drug disposition than simply the half-life. The clearance of the drug is slow and the volume of distribution is approximately 2 L/kg, indicating that it is widely distributed in the body (2). This raises the possibility that the drug or its metabolites could be distributed to the ovary or uterus, organs vital for reproduction. Letrozole is mainly bound to albumin as a carrier protein in the blood. The PDR warns of fetal toxicity in rodent studies at doses of 0.003 mg/kg (about 1/100th the human dose) where increased intrauterine mortality, increased fetal resorption, increased post-implantation loss, decreased numbers of live fetuses, fetal anomalies fetal anomalies including shortening of the renal papilla and ureter dilation and incomplete ossification of the frontal skull and metatarsal. In rabbits, Letrozole was embryotoxic at doses of 1/100,000th and fetotoxic at doses 1/10,000th of the maximal recommended human dose. Thus, standard experimental models showed that Letrozole is toxic to the fetus. The PDR considers Letrozole to be a Category D drug in pregnancy (Positive evidence of fetal risk). Anytime a drug is Category D, the benefits must clearly outweigh the risks. Data on the health on the babies would certainly help to determine this. While the patients are not technically pregnant at the time they are taking the drug, can we be absolutely certain that it or one of its metabolites is no longer in the body especially given the low doses that are toxic in experimental animals?
From: Femara (Letrozole) as a Fertility Treatment: Potential Risks

AIs may be a viable option to replace CC in the
future as the new primary treatment for ovulation induction and in combination with FSH for assisted reproduction procedures. However, larger randomized controlled studies are required to determine the best treatment regimen. If such large studies confirm effectiveness and safety, the use of AIs for ovulation induction would be the first improvement in oral ovulation induction in decades.
Aromatase Inhibitors for ovulation induction
Casper and Mitwally, Sunday, August 21, 2005

Acupunture Update

Just a quick post to let you know that acupunture treatment went well and I had lots of points of pain in my abdomen that she treated. Overall the diagnosis is: spleen qi deficiency, damp accumulations, phlegm obstruction and blood deficiency. Nice eh?

She worked a lot on points to help dry things up, and being that she asked how I was doing, of course I cried. It was weird to have my sinuses drying even as I had just been crying.

I'm going to take this month off to work on the fibroid with herbs. I'll feel much better about things if I do (and chances are that if I don't I won't conceive anyway since my body is disrupted enough to start growing another fibroid). Keep your fingers crossed for me that it helps.

Empty Arms

An online acquaintance (Zuzu) created this beautiful and sad movie about infertility that you should experience. It is deeply moving and perhaps it helps to express how you are feeling, or if you are someone who hasn't experienced infertility, maybe it can help you understand a little more.

Empty Arms

Spleen Qi Deficiency and Liver Qi Stagnation

I came across this the other day and it sounded like me:

Stagnation of Qi and Blood

Poor Liver function can lead to stagnation of Qi and eventually Blood. Stagnation of Qi is experienced in the body as a feeling of fullness, discomfort, or pain in the chest, belly, or head, and in the mind as agitation, nervous tension, suppressed emotion, and frustration. Stagnation of Blood is experienced as a localized stabbing or cutting pain. If this stasis of Blood persists for too long, it gives rise to hard lumps, masses, tumors, or chronic inflammation in the chest, abdominal and pelvic region. A mass or lump may come and go unpredictably, like an intestinal spasm when Qi is obstructed, or may become a benign or malignant tumor in the final stages when Blood becomes "congealed". This situation is often the case in women who develop uterine fibroids, uterine hemorrhage with large clots, irregular, scanty, or suppressed menstruation, cervical dysplasia, ovarian cysts, or tumors.

Stagnant Qi can also obstruct the Spleen, affecting its ability to generate and distribute moisture and nutritive essence in the body. This impairment of Spleen function results in the accumulation of Dampness and an attrition of vitality. The fluid excess itself then may become a secondary source of stagnation since it impedes the flow of Qi. The body often generates Heat to counteract this fluid excess by drying it. This Heat then accumulates and intermingles with the Dampness. Damp Heat can settle in the pelvis, where it damages and obstructs the Blood. Over time this will lead to coagulation and deficiency of Blood. Damp Heat in the Liver also sets the stage for problems such as genital and perianal herpes, jaundice, and hepatitis.

and this:

Although a blood stasis condition is slow to develop initially, once it is entrenched it can recur easily when it is triggered and aggravated by factors leading to Liver Chi Stagnation.
From: Ovarian Cysts and Chinese Medicine

As for my new fibroid, I'm thinking of talking to my acu about it, perhaps it is related to an ongoing issue of spleen qi deficiency that I have symptoms of -- anemia, excess phlegm, get sick all the time, poor digestion, fatigue, allergies, copious EWCM, fibroids and even my bad PMS/breast pain. These symptoms are all related in chinese medicine to the same pattern, blood deficiency, dampness, blood stasis, spleen qi deficiency and liver qi stagnation. Since the symptoms have continued and I've got a new fibroid I think that its even more likely that I have an underlying issue that continues, yes that and a genetic predisposition to fibroids.

The other day I coincidently decided to search out more about digestive disturbances related to Spleen Qi deficiency and suddenly a lot more became clear (and I'm so not surprised to hear that there is a new fibroid in there). Here are some links with info about herbs and dietary changes to help deal with Spleen Qi deficiency:

UNDERSTANDING CFIDS FROM A CHINESE PERSPECTIVE

Digestive Issues

Applying Dietary Therapy

Help for Holiday Digestive Woes

How Do You Treat Intestinal Gas?

Common things I'm seeing on these pages are:

ginger, oatmeal, cooked foods
stay away from sugar, salt, fried foods, stress, fermented foods, citrus (but I like oranges!)

Kinda like my acus told me. I started my search with this string if you are interested to see more: "spleen qi deficiency acidophilus"

Here's a link to a q&a about miscarriage with Randine Lewis where she mentions spleen qi deficiency.

Introducing my new fibroid

I just had my RE appointment this afternoon and it was an interesting experience. My partner basically laid it out there for her, that we were feeling that it was worse to get pregnant than to not get pregnant -- since losing the pregnancies was far worse than not having them. She suggested that we try using Femara to induce ovulation for a few cycles, in the hopes of promoting a stronger ovulation. After a few cycles we could then move on to trying IUI. She said that really, in spite of my partner's poor morphology, that getting pregnant on our own really was the ultimate test of his fertility.

We also discussed and scheduled a HSG for next week, to check for adhesions, any damage to the lining from the two d&cs and make sure the tubes are open. Sounds reasonable, and its what I wanted.

I brought up again that I had read that low ferritin had been linked by some doctors in Britain to lower fertility and increased miscarriage rates and she dismissed me and said that she had never heard that and it wasn't something that she would check for on her own. If I pressed she would do the bloodwork but whatever.

Then she suggested that we do an ultrasound right then and there to see about any new fibroids. Sure I thought, but there weren't any when I had my ultrasounds around the last miscarriage. Low and behold, there was a brand new 2.5 x 3.5 cm intramural fibroid, but away from the uterine lining and towards the outer wall of my uterus. I was in total disbelief. I just went through major abdominal surgery just 14 months before, and there wasn't anything on the scan last June. How could this happen so fast, and in the same are of my uterus?

She said it seemed to be pushing the right ovary out of the way a bit, distorting it on the scan. How nice eh? She said she doesn't think it is causing me any problems right now. She also checked my lining via ultrasound and said that it didn't appear inconsistent which can sometimes be an indicator of adhesions. I'm going to have an HSG on Tuesday next week to check my tubes. If that all looks okay then we'll try for a few cycles using Femara/Letrozole to see if maybe there is an ovulation dysfunction that we can override.

As my doctor was leaving the operatory I said dryly, "well at least I've been growing something in there," and she totally didn't know what to say but then she laughed (my twisted sense of humor overwhelms them you see).

So what should we name this new little interloper?


Some of the lovely things you find in the RE's office.

A few raindrops turn into a downpour

I went to my niece's first birthday party last night. I've written about how uncomfortable I've been around her, starting during her mother's pregnancy as I lost mine.

The baby was being a pill last night, she was really clingy with her parents and didn't want to hang out really with anyone else. It didn't help that my period showed up yesterday (and wasn't it a full moon or just about as well?) After dinner we gave our presents, a dress I bought at the Lavender Festival last summer, plus a box to store baby keepsakes in and then a photo album in which I placed a bunch of our photos that they didn't have. Then my partner and his brother started playing the piano and guitar together doing old covers and my mother-in-law and I law on the couch. I was soooo tired with the cramps and drop in hormones and all, plus too much socializing all week long.

Then it started, just a couple tears at first which I subtly wiped away pretending my eyes were tired or itching. It's okay, I thought to myself, maybe just letting a little bit out will help me feel better. But as I continued to sit there, the feeling of not being acknowledged for my losses began to swell and gradually I couldn't contain it any more.

I walked over behind my partner who was facing the wall near the piano and whispered in his ear that we needed to go because I was crying. He nodded and then turned his face as he played and kissed my cheek through my hair that I was using to cover my face. At the end of the song he got up and said that it was time for us to go, I was already by the door with my things, and he quickly said goodbye. His brother came over to open the door and saw I was crying and asked if I was okay to which all I could say was its the anniversary of my dead babies not being born, how could I be okay? Which he didn't understand at all as he called after me as I walked into the darkness outside, "what? what?"

I totally lost it then as we drove back home, coughing and crying. My partner understood though, I was grateful for that. I told him that I couldn't keep holding it back, especially around his family since I don't really get any acknowledgement from them because I don't know how to talk to them about it. I told him that I thought that in some ways it was healthier for me to not be around babies and small children because then I could just focus on the me I am and not the me that I'm not, the losses that I've had in that area.

When we came home I continued to cry and it came to me that this time of year, with my two due dates going by without my even being pregnant, it's like having to keep driving past the finish line that you never get to cross.

Now that the family has seen me cry though, the first time I think, I don't know what to do. My instincts are to avoid them now because they couldn't possibly understand having never experienced this type of loss themselves. My other thought is to send them an email, my family and friends as well, and point out to them that January 23rd and February 13th are a time of mourning for me and that I just need a little acknowledgement of that. But I just don't know how that would go over.