Fertility and Cyclophosphmide (Cytoxan)

FERTILITY AND CYCLOPHOSPHAMIDE (Cytoxan)

(Compiled from various sources by a non-medically trained person. Last updated 22 April 2006)

In each individual 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 help decide on a course of action.

Male Fertility

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.
Brief exposures to cytoxan may not completely destroy male feritility.

Female Fertility

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.

Eggs and Maturation

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.

Loss of Female Fertility

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.

To preserve female fertility, it seems there are about nine 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.

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.

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.
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 such as Antagon or similar).

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 (Depo Provara, or similar) 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.

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.

(8) Implanon is a small plastic rod containing the hormone progestogen which is inserted just underneath the skin of the upper inner arm and provides protection against pregnancy for the three years it is left in place.

Whether it prevents damage to eggs when a patient is on Cyclophosphamide is not known to the writer.

(9) 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 the above listed 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.

(6) 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.

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

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