Fertility Preservation in Women and Men With Hodgkin Lymphoma

Lymphoma is cancer of lymphocytes, the cells that are part of human immune system. The disease was first described in 1832 and can start anywhere lymphocytes are found (lymph nodes, spleen, bone marrow, or digestive tracts). Two types are recognized; Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). The American Cancer society estimates that approximately 3800 women and 4600 men will be diagnosed with HL in 2010. The majority of those diagnosed with HL are children and young adults (age 15 to 40 years). Modern treatment carries high survival rates. (>80%). HD, however, by virtue of the disease itself or its treatment poses considerable risk to fertility in women and men, especially if it recurs after treatment.

When HD is suspected usually because of enlarged lymph nodes or other symptoms such as a fever, weight loss or night sweating, a biopsy of lymph nodes is required for the diagnosis. Biopsy require special stains (CD15, CD 30) for proteins on the surface of the characteristic cell. Once confirmed certain imaging studies (especially PET scan) to detect the extent of the disease.

Chemotherapy for Hodgkin Lymphoma; combination chemotherapy is used either ABVD, BEACOPP or MOPP-ABV. Each of the letters represent one medication. The combination of drugs is used for several cycles usually 3 to 6. This is the principle treatment for HL.

Radiation therapy using external beam is sometimes combined with chemotherapy. Radiation is usually localized to the area of the body that harbors enlarged lymph nodes.

Hematopoietic stem cell transplantation (HSCT). This treatment is used for resistant HL or HL that recurred after successful treatment in the past (relapse). This treatment requires 1. very high dose of chemotherapy and possibly total body radiation then 2. transplantation of the mother cells of the bone marrow that produce our blood cells. The sources of these cells could be the person himself (autologous) a donor person (allogenic).

Effects of Hodgkin Lymphoma and treatment on future fertility. It has been shawn that men and women attempting conception after treatment for HL had lower chances of becoming pregnant than general population (Aisner 1993).

Men: There is evidence to suggest that HL itself can affect sperm production in 50 to 70% of boys and men, probably due to disturbance of the immune cells. Chemotherapy also can be harmful to sperm production. Alkylating agents especially cyclophosphamide can cause prolonged or permanent azospermia (no sperm production). The other agents may have a reversible effect with some prospect to recovery after months to years. The final effect of chemotherapy is difficult to predict and is related to the type of regimen and doses used. For example the old MOPP regimen for 6 or more cycles result in very high rate of azospermia while the newer ABVD regimen usually causes reversible azospermia.

HSCT entails the use of high dose of alkylating agents and sometimes radiation. It commonly result in prolonged azospermia. HL or its treatment may also affect sperm quality (sperm shape and motility) in addition to concentration. Suppression of sperm production in the testes using a group of medication called gonadotropin releasing hormone agonists (GnRHa) has been suggested but there is no proof that they protect the gonads from the effects of treatment in men and women. The testes should be sheilded from the radiation feild whenever possible.

Women: Chemotherapy for HL can result in reduction of ovarian reserve and may reduce future fertility depending on the medication used, dose, frequency, intensity, age and associated radiation treatment. Multiple studies suggested that the risk of loss of fertility is related to 1. Age > 30 years (or > 25years with hifg dose therapy) 2. Type of chemotherapy. MOPP was associated with loss of fertility than ABVD and BEACOPP. 3. Dose and frequency of chemotherapy. Dose escalation BEACOPP used in more advanced HL was associated more with ovarian failure. 4. Exposure of the ovaries to radiation. In a large study about 20% of women experienced menopause. In another study about 40% of women were able to conceive after treatment. In general published literature is not accurate in reporting fertility potential becaus they used menses as as their end point. Resumption of menses after chemotherapy does not accurately reflect fertility potential. The high dose of chemotherapy used prior to HSCT is associated with ovarian failure in the vast majority of women and girls.

Options for preservation of fertility in men. 1. Sperm cryopreservation: This is a widely available and safe option in adults. One or multiple sperm samples are obtained and frozen for later use. After remission the sample is thawed and used for intrauterine insemination or in vitro fertilization. If IVF is used a single sperm is injected directly into a partner oocyte (ICSI) and the rest of the sperm is refrozen. ICSI is a very powerful tool that can compensate for lower quality sperm encountered in men with HL. In prepubertal boys, sperm may be found in the ejaculate as early as 12 years. Asking prepubertal boys to produce a sperm sample may carry some ethical consideration. The majority of cancer patients are interested in knowing their option about preservation of genetic parenthood in the future. In spite of that, only about one quarter freeze their sperm, mainly because of lack of information about sperm freezing (Schover at al 2002). A survey of over 700 oncologists indicated that less than half offer this option to their patients diagnosed with cancer. 2. Surgical sperm retieval (TESE). Testicular sperm extraction is a surgical procedure where a small amount of tissue is harvested directly from the testes to obtain sperm. Its used in men with azospermia before starting treatment. The specimen is frozen for future use with IVF-ICSI. This is a common procedure in adults and has been reported in prepubertal boys. 3. Testicular stem cell freezing; either within testicular biopsy or separated cells. This is an experimental method with no reported human pregnancy. It is considered for prepubertal boys. The cells or tissue is later transplanted back for sperm production.

Options for preservation of fertility in women.

1. Embryo freezing. This technology is widely available and suitable for women with a partner (or accepting donor sperm) and treatment can be delayed for 3 weeks. It require stimulation of the ovaries and egg retrieval (an outpatient procedure under sedation). Embryos can be frozen for a long time and transferred after remission when fertility is desired.

2. Egg freezing. Used in women with no partner and declining the use of donor sperm. It also require ovarian stimulation and a treatment delay for 3 weeks. Its generally less successful than embryo freezing, although the use of vitrification method can yield comparable results to embryo freezing.

3. Ovarian tissue freezing. This method is experimental. Its used in prepubertal girls or in women that need to start treatment urgently and do not have the time to undergo ovarian stimulation. Its also considered in women or girls before undergoing HSCT since it is associated with very high rate of ovarian failure. One ovary is harvested usually using minimally access surgery (laparoscopy). Patient is diacharged the same day and can start treatment immediately. The ovary is processed so that the outer part (2mm thin) is isolated and frozen. The inner part of the ovary (does not bear eggs) is submitted for pathological examination. After remission the ovary is transplanted back in the abdomen or under the skin.

Women and men diagnosed with Hodgkin Lymphoma experience high chance for cure. Counseling about fertility issues before treatment can enable them to preserve their sperm, eggs or embryos for future use after treatment.

Amr Azim is a board certified reproductive endocrinologist and fertility specialist in New York City IVF and author of many scientific publication in the area of fertility treatment and fertility preservation. I specialize in helping women and men with fertility counseling, testing and infertility treatment including IUI and IVF.
I am very passionate about helping women, men and children diagnosed with cancer and other diseases understand the impact of disease and its treatment on future fertility.
I write regularly at http://nycivf.org and http://preservationoffertility.org

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