Apparently the effect that Cyclophosphamide has on the ovaries is

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					                  Fertility and Cyclophosphamide (Cytoxan)                    30 December 2003

                 (Compiled from various sources by a non-medically trained person))

Cytoxan affects men more immediately than women. Men make sperm continuously throughout
their life. An accumulating amount of Cytoxan eventually destroys the sperm generating cells
resulting in permanent male infertility. Sperm can be banked prior to starting treatment with Cytoxan
and so one can father children by in vitro fertilization even after becoming infertile, but fertility once
lost can’t be restored to males.
Cancer patients have provided most of the experiences with Cytoxan therapy. They are likely to get
very large doses over a short period of time. WG and other autoimmune vasculitis patients tend to
have smaller doses over possibly longer periods depending of course on individual situations.
It seems the effect that Cytoxan has on women is not related to the strength of dose but more to the
length of time a woman is on it. It seems even small doses over a long period are more damaging to
fertility than several big heavy doses.
At birth, a woman has her entire lifetime supply of eggs. These deplete with each menstruation. In
a normal monthly cycle maybe as many as six to fifteen eggs are developing. This means that the
cells surrounding the egg cells divide and start doing their job of preparing the eggs to shed. Of all
the eggs, one or two actually bud off and are available for fertilization. The other remaining eggs
would normally be held ready for the next monthly cycle when others would join them in the
development process, next in the queue as it were. Normally this process continues throughout life
until a woman runs out of eggs. It’s then she undergoes menopause.
All retained matured eggs are lost at each ovulation instead of one or two because the Cytoxan kills
the developing cells supporting them. Eggs that have not yet started to develop will be unaffected
until they are involved in a menstrual cycle. Cytoxan works by stopping cell division of rapidly
dividing cells, so one effect is to kill the supporting cells of the ovary that bring the egg cells to
maturity. In this way the woman’s lifetime supply of eggs gets used up rather quickly. What
Cytoxan does is to speed up the rate at which a woman’s immature eggs are depleted.
The overall effect is to bring forward the date of menopause. When a woman comes off the
Cytoxan, she will still have fewer eggs than she would have had, had she not taken Cytoxan. The
result is that a woman can expect to go into menopause earlier.
When one becomes infertile depends on age. Older women have fewer remaining eggs and those
get used up more quickly when on Cytoxan than would be the case for younger women taking the
same dosages. Younger women have more eggs when starting treatment and so are likely to have
some left when treatment stops.
One can get some idea of when she would normally go into menopause by finding out at what age
her mother and maternal grandmother went into menopause. Most women follow the same kind of
pattern as mothers etc. If they entered menopause late then they likely have more eggs than
average.
Ovarian failure is more of an issue in women closer to menopause than younger. Even so, there
have been varying reports of Cytoxan-induced ovarian failure in younger women. Pulse Cytoxan
therapy in treatment of SLE [Lupus] has suggested that up to 40% of women receiving Cytoxan
before 40 years of age may develop ovarian failure within a 36-month period. This has been
reported in Cytoxan doses varying in total from 3-65g.




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To preserve female fertility, it seems there are seven alternative approaches:

   (1) The most dramatic and perhaps the most effective is to try and save some fertilized eggs.
       This is more easily done if you have a partner and the egg can be fertilized straight away and
       then frozen. This is the usual in vitro fertilization (IVF) technique.

   (2) Freezing unfertilized eggs (immature oocytes) is more problematic because to have much of
       a chance of survival the eggs are best taken and frozen with a section of ovary containing
       the supporting cells. This involves invasive surgery with attendant risks.
           a.   Certainly gamete storage has been done. Some labs have successfully performed
                immature oocyte cryostorage (freezing).     These immature oocytes are less
                susceptible to damage than mature oocytes during freezing but this involves taking a
                wedge of ovary with eggs and preserving it. That in surgery is rather an invasive
                procedure.
           b. In Vitro Fertilization (IVF) of the previously frozen oocytes is unfortunately still
              experimental, although it has been done. However, there has been very limited
              success in achieving pregnancies with this technique. Other ways of preserving
              ovarian function have been tried that are still largely experimental.
           c. See http://www.ivf.com/boston.html for more detailed information on egg
                 preservation.

   (3) One can use a drug treatment that inhibits the functions of the ovaries as a pretreatment,
       such as Gonadotrophin-releasing hormone and agonists (GnRH agonists). These work by
       effecting the endocrine system and pituitary gland. They slow down the growth of cells in the
       ovary and so protect them from the effect of the Cytoxan to some degree. The only problem
       is those drugs also affect everything else and so have a lot of side effects, most notably
       causing osteoporosis.

   (4) The use of the oral contraceptive pill that has the effect of slowing down the whole process
       but acting in a different way so similar to the above only less drastic in the way of side
       effects. But, unfortunately it is also not quite as effective as the 3rd option.

   (5) It may be possible to substitute a less harsh immunosuppressant, for example, Methotrexate
       instead of Cytoxan. This is not always possible as a patient may require Cytoxan to
       effectively treat the disease. Even low dosage Methotrexate may deplete eggs faster than
       normally. A decision would have to take into consideration the woman’s age and her
       physician’s judgment about the risk versus reward aspects of using Methotrexate rather than
       Cytoxan.

   (6) It’s worth investigating if use of newer monoclonal antibodies such as Enbrel, Remicade,
       Humira, Rituxan, Zenapax, etc. can be substituted for Cytoxan. That would depend on the
       particular patient’s disease and tolerance of the selected monoclonal, as well as the effect of
       the monoclonal AB on ovulation. Consultation with at least two physicians experienced in
       the effects of those medications on fertility would seem prudent.

   (7) Recently (June 2004) a successful transplant was made of ovary tissue that had been
       removed and frozen prior to treatment with cyclophosphamide. The transplanted tissue
       produce the hormones needed to trigger production of eggs, and a successful pregnancy
       occurred. This is still experimental, so it isn’t a procedure readily available yet.




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   (8) The last option is of course to accept fate and hope that the patient will not be on Cyclo-
       phosphamide for too long, and will not need it again for due to relapse, or only minimally in
       future relapses.

Considering all these options:

   (1) Saving Some Fertilized Eggs seems to be a bit traumatic and even after all that has no
   guarantees. Perhaps in a few years obtaining and freezing the eggs will become less
   experimental and might be worth a look.

   (2) Freezing Unfertilized Eggs has too many side effects.

   (3) Gonadotrophin-Releasing Hormone And Agonists would seem the most likely but it is not
   a hundred percent guarantee either. At most it might extend the date of menopause a little so
   could be worth doing, as the side effects and action of the contraceptive pill are well known.

   (4) Use of an Oral Contraceptive Pill may be effective in some cases where it is applied,
   though positive results are not guaranteed.

   (5) Substitution Of A Less Harsh Immunosuppressant seems to be a reasonable alternative
   if the effects on fertility are minimal and the treatment is effective.

   (7) Newer Monoclonal Antibodies would seem to be perhaps the best depending on the side
       effects of the monoclonal antibody used, and on it’s effectiveness in treating the autoimmune
       vasculitis.

   (8) Transplantation of ovary tissue is not an option presently available except perhaps
       experimentally.

   (9) Acceptance is the default option, to accept the probable early menopause, with adoption
   remaining an option.

In each case of autoimmune vasculitis, a woman (and her partner?) must consider the options in
discussions with a fertility specialist and perhaps the woman’s rheumatologist to decide on a course
of action.




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