Clomiphene For Women Over 35: A Bad Idea

29 May
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Clomiphene citrate (Clomid) is by far the most commonly used fertility drug in the world. Used in the right circumstances and with appropriate application, it can be and is effective in assisting conception.

Ideally the use of clomiphene should be confined to younger women (under 35 years) who have normal “ovarian reserves” ( as evidenced by normal day-3 FSH, Inhibin B or antimulerian hormone[AMH] levels) and accordingly are most likely to respond by producing the multiple follicles (more than 3) necessary to override the “antiestrogenic” effects of clomiphene (see below). If used for longer than 3 consecutive months, clomiphene is not only ineffective, but actually starts to function as a “relative” contraceptive! This is a shocking revelation to many women that I consult with who have often done 6 or more consecutive cycles of Clomiphene without success.

Few realize that the rate of conception with clomiphene therapy is about 1/3 lower than the natural fertility rate for any given age and about 25% lower than when gonadotropin stimulation is used. This problem increases significantly with advancing age . Consider the fact that in women under 35 years, the pregnancy rate with clomiphene treatment is about 10% per cycle , about 5% between 35 and 40 years and 2% after age 40. Here are a few reasons why:

  1. Clomiphene through its “anti estrogenic effect” tricks the hypothalamus into thinking that estrogen levels are low. In response, the pituitary gland releases an exaggerated amount of follicle-stimulating hormone (FSH), which stimulates development of the follicles, ultimately resulting in ovulation. The growing follicles secrete estrogen into the bloodstream, thus closing the feedback circle that the hypothalamus initiated in response to the anti-estrogen properties of Clomiphene. Unfortunately however, at the same time the pituitary also releases large amounts of LH which causes the ovary to produce large amounts of the male hormone testosterone. In high local concentrations, testosterone can compromise egg quality and thus ultimately the chance of having a baby. The older the woman, the greater this adverse effect of clomiphene will be.
  2. Clomiphene’s anti-estrogenic effects often manifest as an over-thin uterine lining that is incapable of supporting a healthy pregnancy, thickening of the cervical mucus, making sperm migration via the uterus to the awaiting egg in the fallopian tube difficult or impossible. This antiestrogenic effect will invariably build to such a degree over 3 consecutive back-to back cycles of clomiphene therapy (that regardless of age or “ovarian reserve”) most women will manifest with such effects by the 4th month of back-to-back cycles of stimulation. This is why no one using clomiphene should do more than three consecutive cycles of treatment without taking at least a break in therapy. Fortunately, the cessation of Clomiphene treatment for only one (1) month is usually sufficient to completely reverse such highly undesirable side effects. The same anti-estrogen effects can occur with the very first clomiphene treatment cycle. This usually happens in women over 35 years and those with elevated FSH levels (poor responders) who cannot produce enough follicles that would produce sufficient estrogen to overcome the anti-estrogenic effects of clomiphene. When this happens or when the woman fails to conceive following (at most) 3 cycles of clomiphene stimulation, it is time to move on to a different method of treatment.
  3. Twenty percent of clomiphene cycles are associated with trapped ovulation (LUF syndrome). This means that in spite of hormone changes suggesting that ovulation has occurred, the egg remains trapped in the ovary. Obviously this is not condusive to the establishment of a successful pregnancy.The above serves to explain why I strongly hold that Clomiphene should not be prescribed to women over 35 years of age, never to women with diminished ovarian reserve or women over 40 years, and should be avoided in IVF (alone or in combination with gonadotropins). The results are simply too poor to validate such practices.

23 Comments

  • Jelena says:

    I am 42 and I have to children (ages 2 and 6). I have been diagnosed with low ovarian reserve. My cycles have always been clockwork-normal and I do ovulate most months (based on my ovulation predictor strips). My husband is 39 and we have been trying for our third child for over a year. We have also had an inordinate amount of stress during much of this time. I was prescribed Clomid before two IUIs with injections. They failed and my 27 day cycle went down to 20 days. It is now three months past the last Clomid cycle and my cycle is now up to 25 days. Could I have harmed my chances for pregnancy because of the Clomid? Should I find a new doctor? Do you think there are other treatments for me before jumping into IVF?

    • Geoffrey Sher says:

      Hi Jelena,

      The clomiphene will not have done irreparable harm. However, in my opinion, it is not advisable to use clomiphene when you are over 40Y. The baby rate per cycle is about 1:50 and you do not have the luxury of time for such a small return. Additionally, in my opinion, clomiphene should not be used in women with DOR. You need IVF and because of the time crunch, I would suggest Staggered IVF with Embryo banking (see below).

      Please go to the home page of this blog, http://www.IVFauthority.com . When you get there look for a “search bar” in the upper right hand column. Then type in the following subjects into the bar, click and this will take you to all the relevant articles I posted there.
      1. “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)

      2. Ovarian Stimulation for IVF: The most important determinant of IVF Outcome” (Nov. 2103)

      3. “Agonist/Antagonist Conversion Protocol”

      4. “Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)

      5. “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)

      6.“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)

      7. “IVF success: Factors that influence outcome”

      8 “Use of the Birth Control Pill in IVF”

      9.”Staggered IVF”

      10.“Embryo Banking”

      11.“Array CGH versus metaphase CGH in IVF patients….’

      12.“Egg Donation”

      Consider calling 800-780-7437 or 702-699-7437 to arrange a Skype with me so we can discuss your case in detail.

      Finally, perhaps you would be interested in accessing my new book (recently released). It is the 4th edition (and a re-write) of “In Vitro Fertilization: The ART of Making Babies”. The book is available through “Amazon.com” as a down-load or in book form. It can also be obtained from most bookstores.

      Geoff Sher

      P.S: Please go to http://www.youtube.com/watch?v=Vp3GYuqn2eM&feature=youtu.be
      To view a video-tutorial by Linda Vignapiano RN, Clinical Manager at SIRM-Las Vegas.

  • Bailey says:

    Hi Dr. Sher,

    I am 33 and had my first pregnancy end in miscarriage last October. Since then I have had no luck with getting pregnant. In February my OBGYN suggested clomid at 50 mg (days 5-9) and my day 3 FSH was an 11 which she said was normal. Day 21 progesterone showed 8 so she bumped me up to 100mg the next cycle. I actually took the next cycle off and started the following cycle. No luck with pregnancy and Day 3 showed my FSH jumped to 22. She said to continue to take the clomid 100mg for a 3rd cycle but didn’t the clomid make my FSH jump to 22? She stated the clomid does not affect the Day 3 FSH. I have an appointment with a RE this Sunday so if I am on the clomid I am sure he can monitor me, right?

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