Hematologic malignancies (leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloma and myelodysplastic syndromes) affected an estimated 139,860 people in the United States in 2009. However with continued research progress in the treatment of these cancers, mortality rates have steadily decreased since 1996.[i] [The Leukemia & Lymphoma Society. June 2009.] Chemotherapy remains the mainstay of treatment for most patients. Generally a combination of oral or intravenous drugs are used that, while effective in destroying rapidly-dividing leukemia and lymphoma cells, also affect other rapidly replaced normal cells in the body including red blood cells, gastrointestinal mucosa, hair cells, and gonadal tissue. In cases of lymphoma, radiation may be used as well to shrink focal areas, collections, or masses that cause pain or limit the function of adjacent organs. In addition, immunotherapy has become an important tool in the management of both leukemias and lymphomas.
In more serious cases of hematologic cancer, both high-dose chemotherapy and radiation therapy are applied to the whole body to eliminate both normal and abnormal hematopoietic cells of the body in preparation for the transplant of healthy bone marrow. The process of bone marrow transplantation leaves the patient immunosuppressed, requiring extensive hospital stay and contact precautions. In patients receiving donor bone marrow cells, graft-versus-host disease (GVHD) may develop, whereby donated white blood cells react against the patient’s normal tissues. The reaction can range from mild to severe and can occur even years after the transplant. Due to the toxic effects of treatment, even those in remission from a hematologic cancer require continued surveillance for secondary malignancy, making the treatment of hematologic cancer one which leads to significant physiologic and psychological fatigue.
Case reports of altered sexual functioning following cancer therapy are often related to cancers that directly affect reproductive or sexual organs, such as ovarian or breast. Very few discuss the sexual dysfunction encountered by women after being treated for hematologic malignancies. In the medical literature, sexual dysfunction is overshadowed by concerns of infertility for survivors of hematologic cancers; infertility, though related, will not be discussed here.
As hematologic cancers are not limited to a single area of the body, its treatment relies on the use of systemic modalities such as combination chemotherapy, total body irradiation, and hematopoietic stem cell transplant (HSCT). Consequently reproductive organs and the hypothalamic pituitary axis responsible for their function are often affected and many women develop amenorrhea and some degree of ovarian failure.
Many of the induction agents used to eliminate cancer cells are gonadotoxic. Gonadotoxicity is especially associated with cyclophosphamide, a popularly used agent in the treatment of many leukemias and lymphomas.[ii] [Meirow D, Nugent D. Hum Reprod Update. 2001; 7:535-543] Damage is dose-dependent and can occur as early as 72 hours following the last dose of chemotherapy.[iii] [Chatterjee R, Mills W, Patel A et al. Br J Haematol. 1994; 88(S1):82] Theca and granulosa cells located in the ovary are responsible for the production of sex steroids; any process that interrupts theca and granulosa cell function prevents the production of androgens associated with sexual desire and estrogen needed to prevent vaginal atrophy and dryness. Direct damage to the ovary by chemotherapeutics and radiation reduces the total number of follicles in the ovary such that a woman may regain sexual function in the immediate years following her treatment, but may also suffer from early onset menopause (before the age of 40) and its associated sexual problems.[iv][ Chiarelli AM, Marrett LD, Darlington G. Am J Epidemiol. 1999; 150: 245-254] Women with premature ovarian failure have fewer sexual fantasies, decreased arousal, and increased genital pain; however the frequency of desire to have sexual contact does not differ from that of the general population.[v] [Van der Stege JG, Henk G, van Zadelhoff SJ. Menopause. Jan 2008. 15(1): 23-31]
Indirect alterations in sexual function also result from anemia caused by chemotherapy and the emotional instability and fatigue entailed by treatments that require frequent and intensive hospitalization. Diagnoses of premature menopause or premature ovarian failure may also independently cause psychological distress with effect on sexuality.
Sexual dysfunction is greatly impacted by the treatment chosen for the malignancy, with no significant difference in outcome based on disease type.[vi] [Kiserud CE, Schover LR, Dahl AA, et al. Clinical Oncology. 10 Dec 2009; 27(35)] Most cancer treatments with obvious effect on sexual function are provided to patients with gynecologic cancers that tend to present later in life. However the hematologic cancers are unique for comprising nearly one-third of all childhood cancers.[vii] [Graziottin A, Rosemary B. Menopause. Nov/Dec 2004; 11(6):766-777.]
Consequently young survivors of lymphomas and leukemia may experience sexual development at a delayed pace or different perspective, ultimately leading to sexual dysfunction in later life. One study comparing young female leukemia survivors (mean age at diagnosis of 8.5 years) to age-matched controls highlighted the difference in attitudes about sexuality. Survivors were more likely to endorse the idea of men being the initiators in sexual relationships, less likely to have had sexual intercourse, less likely to masturbate or approve of masturbation, less likely to express sexual desires to partners, and less likely to have enjoyed sexual intercourse despite starting at similar ages and having sex at similar frequencies as controls once initiated.[viii] [Puukko LRM, Hirvonen E, Aalberg V, et al. Archives of Disease in Childhood. 1997; 76:197-202] This study also found that survivors were significantly less likely to be concerned about sexually transmitted diseases, contraception, and pregnancy. These findings may have resulted from previous research findings of adolescents with cancer trying to prematurely adopt what they perceive to be “normal’ behaviors and perspectives.[ix] [Madan-Swain A, Brown RT, Sexson SB, et al. Psychosomatics. 1994; 35:453-9] Consequently young female survivors may put themselves in risky and uncomfortable sexual situations that prevent them from ever adjusting to their inner sexuality, likely leading to sexual dysfunction in adult life.
Though women with pre-pubertal hematologic cancer are more likely to suffer delays in psychosexual development, they are less likely to experience the acute physiologic symptoms of treatment-induced gonadal damage compared to older women. Young women have greater ovarian follicle reserve compared to older woman. They are thus able to tolerate greater gonadotoxic exposure and are more likely to continue creating the estrogen needed to prevent vaginal atrophy and dyspaerunia. For example, one study on the use of cyclophosphamide in Japanese women used amenorrhea as a marker for gonadal dysfunction and showed that women below the age of thirty required at least 20g to induce amenorrhea, whereas women in their thirties and forties required mean doses of 9.3g and 5.2g respectively.[x] [Yeung SCJ, Chiu AC, Vassilopoulou-Sellin R, et al. Endocrine Reviews. 1998; 19(2):144-172] Similarly, older women are at greater risk of symptomatic damage from radiation therapy—Lushbaugh and Casarett report that only 6 Gy are needed to produce permanent ovarian failure in older women, compared to 20 Gy in women under the age of 40,[xi] [Lushbaugh CC, Casarett GW. Cancer. 37: 1111-1125] a recent report of radiation treatment of non-Hodgkin’s lymphoma describing median doses from 30-36 Gy.[xii] [Mohammed N, O’Rourke N. J of Radiotherapy in Practice. 2001; 2:133-138] Thibaud et al further support the risk of greater gonadal damage with age in a study of total body irradiation for bone marrow transplant conditioning in which 12% of patients under the age of 25 were able to recover ovarian function after post-irradiative failure, compared to 0% among patients over the age of 25.[xiii] [Thibaud E, Rodriguez-Macias K, Trivin C, et al. Bone Marrow Transplantation. 1998; 21:287-290]
With respect to gonadotoxics, alkylating agents are well known to impose high risk of ovarian failure.[xiv] [Meirow D, Lewin A, Or R, et al. Fertil Steril. 1997; S218.] Consequently, some research has attempted to find ways to avoid the use of cyclophosphamide by studying protocols of comparable efficacy but lower toxicity. For example, one study found the combination of vincristine, epirubicin, etoposide, and prednisolone (VEEP) to be comparable in efficacy and able to preserve fertility in female patients. Another study has found similar results for ABVD in the treatment of Hodgkin’s lymphoma.[xv] [Yeung SCJ, Chiu AC, Vassilopoulou-Sellin R, et al. Endocrine Reviews. 1998; 19(2):144-172] With respect to radiation therapy, fractionation of the dose has been found to increase the likelihood of return to normal ovarian function by a factor of 4.8 compared to initial high dose therapy. [xvi] [Sanders JE, Buckner CD, Amos D, et al. Journal of Clinical Oncology. May 1988; 6(5):813-818] Though with retained ovarian function, one might assume that these patients experience less sexual dysfunction, however the above studies of alternative regimens did not specifically examine sexual function as related to treatment-induced ovarian damage.
Most of the literature on sexual dysfunction in survivors of hematologic malignancy has emphasized the effect of hematopoietic stem cell transfer (HSCT). Patients with cancers that are unable to be controlled with chemotherapy or radiation alone are candidates to receive HSCT. HSCT is a demanding, highly aggressive process that has a profound impact on quality of life, with invasive medical procedures, toxic side effects, frequent medical complications, changes in body image, protective isolation, and risk of mortality from the procedure itself. Yet more patients are surviving HSCT such that lifestyle considerations for survivors is becoming more of a topic for discussion. Patients immunosuppressed by conditioning treatments and transplants occasionally report fears of acquiring infections causing them to adopt behaviors that isolate them from their partners. Constant hospitalizations further exacerbate these behaviors. For example, patients may become more insistent on the use of barrier protection during sexual relations with trusted partners, constantly wear masks, and avoid kissing. These protective measures interfere not only with sexual behavior, but the expression of sexuality. In some cases these compulsions to protect themselves without open communication with the partner lead to feelings of guilt and resentment which further impair sexual relations.[xvii] [De Souza Melo A, de Carvalho EC, Rotter Pela NT, et al. Rev Lat Am Enfermagem. 2006 Mar-Apr; 14(2):227-32] Long term studies of patients receiving HSCT further endorse the decreased sexual frequency, satisfaction, energy, and positive body image.[xviii] [Mumma GH, Mashberg D, Lesko LM. General Hospital Psych. Jan 1992; 14(1): 43-55] [xix] [Socie G. Blood. Feb 2008; 111(3):972-973.]
Type of HSCT is also a risk factor for future sexual dysfunction. Zittoun et al. compared outcomes for acute myelogenous leukemia survivors receiving allogeneic/autologous bone marrow transplants or intensive consolidation chemotherapy after an average of 50 months of complete remission, finding that one-third of the survivors reported sexual dysfunction—47-68% among allogeneic HSCT compared to 18-30% among autologous HSCT and 15-22% among chemotherapy patients. 28% of allogeneic HSCT patients reported dyspareunia compared to 15% of patients receiving autologous HSCT and 3% of those receiving consolidation chemotherapy. 60% of allogeneic patients reported loss of interest in sex compared to 21% among autologous. 47% of allogeneic patients reported decreased pleasure with sex compared to 18% among autologous. 53% of allogeneic reported decreased ability to even engage in sexual activity compared to 29% autologous. These differences seen between consolidation chemotherapy and HSCT may be due to the requirement of conditioning chemotherapy and/or total body irradiation; radiation can cause fibrosis of the reproductive tract, chronic constitutional symptoms such as weakness and fatigue, and occasional cognitive dysfunction.[xx] [Zittoun R, Suciu S, Watson M, et al. Bone Marrow Transplant. 1997; 20(4):307–315] With respect to the increased report of symptoms among patients with allogeneic HSCT, the chronic requirement of immunosuppressants and the occurrence of GVHD may play a significant factor. Severe GVHD can cause vulvo-vaginal infection with vaginal stenosis and disfigurement of the internal and external genitalia and perineum, leading to decreased perception of attractiveness, desire, and pain-free intercourse.[xxi] [Schubert MA, Sullivan KM, Schubert MM et al. Bone Marrow Transplant. 1999; 5:425-430] [xxii] [Andrykowski MA, Greiner CB, Altmaier EM. British J of Cancer. 1995; 71:1322-1329]
The management of sexual dysfunction after therapy for hematologic cancers is difficult and does not always promise adequate results. Consequently management should be directed at prevention through reducing damage wherever possible. Oncologists may consider using less toxic conditioning regimens, avoiding total body irradiation and alkylating agents where possible. For patients undergoing chemotherapy and high-dose therapy for HSCT, co-treatment with GnRH can help to prevent climacteric side effects.
For patients initially beginning chemotherapy or HSCT conditioning therapies, the use of gonadotropin releasing hormone (GnRH) agonists has been shown to preserve ovarian function by up to 68%.[xxiii] [Clowse MEB, Behera MA, Anders CK, et al. J of Women’s Health. 3 Nov 2009; 18(3)] By adhering to and down regulating the gonadotropin receptors of the pituitary gland, GnRH agonists (leuprolide, triptorelin, and buserelin) prevent the stimulation of the ovaries and the subsequent activity of follicles. As chemotherapy and radiation are most toxic to cells that are actively growing and multiplying, these gonadotoxics will have a mitigated effect on the quiescent ovary. Though none of the studies done on GnRH agonists have been randomized controlled studies and though they have not verified the efficacy of GnRH agonsists to preserve sexual function, the ability to preserve estrogen production alone is encouraging.
Despite use of GnRH agonists, some patients will still experience premature ovarian failure. These patients should be provided the option of hormone replacement therapy (HRT). The timing of hormone replacement therapy becomes just as important as well due to the fact that women who are treated with radiation may experience progressive vaginal fibrosis that will worsen without dilation or intercourse; from a psychosexual standpoint partner relations and sexuality may deteriorate over time without treatment for prolonged sexual dysfunction with HRT. As survivors with premature ovarian failure are at risk of other menopause-related health problems such as decreasing bone density and increased cardiac risk, HRT should be encouraged. A prospective study of HRT showed that among eligible bone marrow transplant patients, HRT was able to improve hot flashes, insomnia, emotional changes, vulvovaginal atrophy, and skin atrophy in more than half of patients and within the course of one month, without complications. These results included the use of both oral and transdermal estrogens based upon the individual desires of each patient.[xxiv] [Piccioni P, Scirpa P, D’Emilio I, et al. Maturitas. 10 Dec 2004; 49(4):327-333] Patients being prescribed HRT should be provided with a cyclical progestin if they have not had a hysterectomy to prevent uninhibited endometrial growth. As hormones modulate the progression of various autoimmune diseases, there has been concern that HRT might be contraindicated in patients receiving allogeneic HSCT due to a theoretically increased risk of graft vs. host disease, however patients are chronically immunosuppressed and will only be taking doses of HRT that would bring their levels to baseline function; allogeneic HSCT patients can thus be offered HRT.[xxv]
The return of sexual function is becoming an expectation in the treatment outcomes of patients with hematologic cancers. Physicians thus have to be more aware of the problem and be ready to counsel patients. One study indicated after surveying HSCT survivors that half of patients had no discussion of possible sexual dysfunction prior to their treatment. Half as well did not discuss sexual function at 1 and 3 years after HSCT. Those who were fortunate enough to enter discussion of sexual function with their physicians reported fewer difficulties.[xxvi] [Mosher CE, Redd WH, Rini CM. Psycho-Oncology. Aug 2008; 18:113:127] Specific to HSCT patients, physicians should advise against resuming sexual intercourse until patient platelet counts rise to at least 50,000/ml to avoid risk of bleeding. Though immunosuppressed patients may continue to have sexual relations, they should also be advised to avoid practices that increase exposure to feces. Condoms are generally recommended as well to prevent sexually-transmitted infections that might have more severe manifestations in the immunocompromised. As HPV can progress at a much faster rate among immunocompromised patients, women should also have regular pap smears. More importantly however, physicians need to provide reassurance to patients. Recklitis et al compared 5- year survivors of Hodgkin’s Lymphoma to their siblings without cancer, finding a nearly identical prevalence of sexual problems and similar ratings of overall sexual satisfaction. 93.1% of the survivors had received radiation therapy for their treatment and 36.8% had received chemotherapy. Though prevalence of sexual dysfunction among survivors of hematologic cancers may be high, they may not be significantly different in number from that of the normal population. Though certainly possible that these survivors face more severe sexual morbidity, their sexual problems can be alleviated with the help of physicians open to discussing them.[xxvii] [Recklitis CJ, Sanchez Varela V, Ng A, et al. Psycho-Oncology. 24 Dec 2009. E-publication ahead of print]