Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section G – Complications of Therapy

Chapter 64 – Reproductive Complications

Tracey O'Connor,Donald L. Trump

SUMMARY OF KEY POINTS

  

   

Reproductive complications secondary to cancer or its treatment are expected to increase as the number of cancer survivors increases.

Cancer-Related

  

   

Oligospermia is present in more than 50% of patients with Hodgkin's disease and testicular cancer.

  

   

Patients with baseline oligospermia are more likely to become infertile following treatment.

Treatment-Related Complications

  

   

Surgery

  

   

Radiation therapy

  

   

Hormonal therapy

  

   

Chemotherapy and bone marrow transplantation

Surgery

  

   

Prostatectomy and other pelvic surgeries are associated with erectile dysfunction; retroperitoneal dissection is associated with retrograde ejaculation.

  

   

Nerve-sparing surgery improves potency and decreases retrograde ejaculation rates in patients with prostate, testicular, and rectal cancers.

  

   

Gynecologic surgery can have a direct impact on sexual function by altering the normal female genital anatomy.

  

   

Altered body image can have a profound impact on sexual function.

Radiation Therapy

  

   

Prepubertal testicles and ovaries are more resistant to the effects of radiation.

  

   

Testicular spermatogenesis is affected by doses as low as 15 cGy, and complete aspermia may occur with a dose of 600 cGy.

  

   

Leydig cell dysfunction occurs at doses exceeding 2000 cGy.

  

   

Ovarian function is more resistant to the effects of radiation. The effects are age related, with a significantly increased risk of permanent menopause in patients older than 40 years at dosages exceeding 150 to 400 cGy.

  

   

Erectile dysfunction occurs by 2 years from treatment in 60% to 80% of prostate cancer patients receiving external beam radiation radiations. The majority are attributed to vascular insufficiency.

Hormonal Therapy

  

   

Gonadotropin-releasing hormone (GnRH) agonists and antagonists result in medical castration with resultant loss of libido and impotence.

  

   

Antiandrogen therapy results in a lesser degree of impotence compared to GnRH analogs in the treatment of prostate cancer.

Chemotherapy and Bone Marrow Transplantation

  

   

Alkylating agents are associated with the highest rates of infertility.

  

   

Doses and duration of treatment are directly associated with risk of infertility.

  

   

Risk of infertility and amenorrhea is related to age, dose, and duration of therapy.

  

   

Prepubertal males and females have the highest tolerance for chemotherapy. Normal puberty has been reported in both genders.

  

   

Premature ovarian failure is age-related, the highest risk being in patients older then 40 years. The younger the female, the lower is the risk of amenorrhea and the higher are the chances that menstruation will resume on completion of chemotherapy.

  

   

High doses of alkylating agents such as cyclophosphamide greater than 7.5 g/m2 are likely to be associated with abnormal sperm count in children. Doses greater than 9 g/m2 are associated with prolonged infertility. The mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) regimen that is used in Hodgkin's disease is particularly associated with male infertility. In some males, fertility recovered several years after completion of therapy.

  

   

Females who resume menstruation after treatment are at higher risk of early menopause.

  

   

Radiation therapy during bone marrow transplantation conditioning results in male infertility and a high rate of premature ovarian failure. Bone marrow transplantation without radiation has been associated with a high rate of fertility preservation in females treated before puberty or at a very young age.

Cancer and Pregnancy

  

   

Cancer complicates 1 in every 1000 pregnancies.

Chemotherapy

  

   

The highest risk of congenital abnormalities is during the first trimester of pregnancy and is especially common with antimetabolites such as methotrexate.

  

   

Data available from leukemia and breast cancer patients suggest that chemotherapy during the second and third trimesters of pregnancy results in normal offspring. No long-term complications have been identified.

Radiation Therapy

  

   

Risks are highest during organogenesis period (first trimester).

  

   

Mental retardation and microcephaly may occur with second-trimester and early third-trimester exposure.

Prevention and Treatment

  

   

Sperm cryopreservation should be discussed with all males who undergo potentially sterility-inducing treatments.

  

   

Use of GnRH analogs may have a protective effect on ovarian function, but no protective effects on spermatogenesis have been established yet. Their use is considered experimental.

  

   

Gonadal shielding and ovarian transposition ameliorate the effects of radiation on gonadal function.

  

   

Assistive reproductive technologies and alternative methods of sperm collection have resulted in successful pregnancies for couples with severe male infertility secondary to cancer or its treatment.

  

   

The use of sildenafil has reestablished potency in a large number of patients with surgery- or radiation-induced erectile dysfunction.

INTRODUCTION

Advances in the treatment of cancer have resulted in marked improvements in survival and cure rates, causing the number of cancer survivors to rise.

Cancer patients often suffer acute and long-term complications related to cancer and its treatment. Insults to reproductive health constitute an often overlooked dimension. Sexual dysfunction and infertility can have a major impact on patient well-being, interpersonal relationships, and family planning.

Attention to reproductive health issues and patient involvement in treatment planning early in the course of the disease and its treatment are key. This review focuses on the reproductive complications of cancer and its treatment.

REPRODUCTIVE PHYSIOLOGY

Gonadal Form and Function

The ovary produces mature fertilizable eggs as well as sex steroids and reproductive/gonadal peptides. These activities are carried out in an integrated manner by the different compartments of the ovarian functional unit, the follicle. The granulosa cells are the source of the sex steroids estradiol and progesterone as well as the peptides inhibin, activin, and follistatin. De novo synthesis of progesterone by the theca cells is dependent on an abundant supply of cholesterol. Granulosa cells also produce progesterone independently.[1] Estrogen biosynthesis, by contrast, requires cooperation of both the granulosa and the theca-interstitial cells. Precursor steroids (mainly androstenedione) synthesized in the theca cells are transferred across the basement membrane of the follicle to the granulosa cells, where they are aromatized to estrogens. The peptides inhibin, activin, and follistatin are expressed in various tissues, including the ovary and anterior pituitary.

Humans have approximately one million follicles at birth. During the reproductive years, typical cyclic follicular recruitment, selection, and dominance eventually deplete the ovary of follicles, leading to cessation of ovarian function and menopause.

In males, the testes secrete androgenic hormones and produce mature spermatozoa. These two processes are highly interrelated and regulated by multiple factors. Much like the ovary, compartments of the testes serve different functions. The seminiferous tubules consist of Sertoli cells that support the developing sperm and germ cells and are the sites for spermatogenesis. The interstitial or Leydig cells are essential for testosterone synthesis. Testosterone is transported from the Leydig cells to the seminiferous tubules, where it enhances spermatogenesis. Testicular hormones are responsible for the induction of male genitalia development during embryogenesis.

Hypothalamic-Pituitary-Gonadal Axis

The main regulators of testicular and ovarian function are the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The biosynthesis and secretion of gonadotropins are modulated by an interplay of hypothalamic factors: gonadotropin-releasing hormone (GnRH), intrapituitary factors (pituitary peptides—activin and follistatin), and feedback by gonadal factors.[1]Gonadotropin expression is controlled by the hypothalamus primarily through the action of GnRH. GnRH is produced in the medial basal hypothalamus and released in a pulsatile fashion to the anterior pituitary, where it binds to plasma membrane receptors on the gonadotropes and stimulates release of FSH and LH. Depending on the reproductive stage, estrogens can either increase or decrease gonadotropin production. Increased levels of estrogen in females or testosterone in males downregulate gonadotropin secretion. However, increased levels of estrogens at the time of LH surge exert a positive feedback effect. In addition to steroid hormones, the gonadal proteins activin, inhibin, and follistatin modulate release of FSH.[2] Inhibin decreases and activin stimulates gonadotropin function. Follistatin also inhibits FSH but is less potent than inhibin.

Regulatory effects of gonadotropins on the ovaries and testes are similar. In the testes, LH interacts with high-affinity receptors on the plasma membrane of the Leydig cells and, through a cAMP-activated series of steps, stimulates the synthesis of the enzymes of testosterone production. The epithelium of the seminiferous tubules is the primary site of action of FSH. FSH binds to cell surface receptors of the Sertoli cells, stimulating the synthesis of androgen-binding proteins and aromatase enzyme complex that convert testosterone to estradiol. LH and FSH effects on the ovaries strongly resemble those in the testes. Activation of gonadotropin receptors on the plasma membranes of the granulosa and theca cells stimulates the adenylate cyclase system, inducing the regulation of female steroid hormone production and follicular maturation.[3]

DIRECT EFFECTS OF CANCER ON REPRODUCTIVE FUNCTION

Although this chapter concentrates on the impact of cancer therapy on reproductive function, it is important to note that cancer can have important direct effects on sexual and reproductive function.

Gonadal tumors can result in reproductive dysfunction secondary to gonadal germinal tissue destruction as well as to aberrations in hormonal balance. Ovarian sex cord–stromal tumors are often associated with hormonal effects such as precocious puberty, amenorrhea, virilizing symptoms, or postmenopausal bleeding. Male sex cord tumors may be associated with precocious puberty, feminization syndrome, and gynecomastia. Reproductive organ cancers and other cancers involving the pelvis may have direct anatomic interference with coitus or indirect interference secondary to pain. Females with invasive vulvar and vaginal cancers and advanced cervical cancers often present with postcoital bleeding or dyspareunia. Males with testicular cancer may have diffuse testicular pain, swelling, and tenderness that interfere with intercourse. Penile cancer usually presents as a penile sore or mass, but when neglected, it can result in ulceration, bleeding, or secondary infection, which can interfere with coitus.

Central nervous system damage by primary or metastatic cancer or indirectly through paraneoplastic involvement can have a considerable impact on reproductive function. Pituitary prolactin-secreting adenomas are commonly associated with impotence in men and amenorrhea and galactorrhea in women. Other pituitary adenomas can affect reproductive function by destroying LH- and FSH-producing gonadotropes. Craniopharyngiomas and other metastatic cancers can directly invade the pituitary gland and produce hypothalamic-pituitary dysfunction. Metastatic disease that affects the hypothalamus-pituitary axis will also lead to reproductive dysfunction. Paraneoplastic syndromes are an infrequent but well documented cause of reproductive dysfunction. Ectopic adrenocorticotropic hormone secretion (e.g., small cell lung cancer) can result in Cushing-like disease including amenorrhea. Other neurologic paraneoplastic syndromes can have a direct impact on reproductive function through the involvement of the autonomic system such as in Lambert-Eaton syndrome or indirectly by resulting in personality changes such as in limbic encephalitis.[4]

Testicular cancer and Hodgkin's disease are among the most common diseases affecting young men of reproductive age, and both are associated with an increased rate of infertility.

Men with Hodgkin's disease may have pretreatment impairment of spermatogenesis. A recent study of patients with Hodgkin's disease reported that 47% had abnormal semen analysis.[5] In this study, semen quality correlated significantly with the hemoglobin level but not with disease stage or fever. In another study of 158 patients with Hodgkin's disease, elevated erythrocyte sedimentation rate and advanced disease stage were associated with poor semen quality.[6] The association between testicular cancer and abnormalities of spermato genesis is even more pronounced. The degree of spermatogenic abnormalities in these patients is greater than can be attributable to local tumor effect or the degree of systemic involvement. A recent study found that sperm count was lower in 83 patients with testicular germ cell cancer (15 × 106/mL versus 48 × 106 mL) compared with healthy men.[7] Histologic investigations have revealed a high prevalence of dysfunctional spermatogenesis even in the contralateral testicle that is uninvolved with cancer.[8] An increased risk of testicular cancer has also been observed in men presenting with an abnormal semen analysis and infertility. Infertile men with abnormal semen analyses have a 20-fold higher incidence of testicular cancer compared to the general population.[9] The specific links between the pathologic events that cause infertility and testicular cancer remain unclear.

EFFECTS OF CANCER THERAPY ON SEXUAL AND REPRODUCTIVE FUNCTION

Surgery

The surgical treatments that have the most significant impact on reproductive function are those involving the pelvis. These include radical prostatectomy, radical cystectomy, rectal cancer surgery, orchiectomy and retroperitoneal dissection, and radical hysterectomy.

Prostate Cancer

Erectile dysfunction in patients undergoing radical prostatectomy is commonly seen after surgery. [10] [11] [12] [13] Steineck and colleagues randomized 376 patients to radical prostatectomy versus watchful waiting; the incidence of erectile dysfunction was significantly higher in the surgical group (80%) versus the observation group (45%).[14] Identification and sparing of the neurovascular bundles that carry cavernous nerves is associated with a significant improvement in potency rate following radical prostatectomy.[15] Bilateral nerve-sparing surgeries are considerably more effective in maintaining erection compared to unilateral nerve-sparing surgeries. Potency rates following bilateral sparing surgery at 3 years were 76% compared to 30% with unilateral sparing surgery in previously potent patients younger than 60 years of age. The rates of potency are lower in older patients and in patients with known erectile dysfunction prior to surgery.[16]

Testicular Cancer

Retroperitoneal lymph node dissection (RPLND) frequently damages the sympathetic nerves that innervate the seminal vesicles and the bladder neck. This leads to loss of seminal vesicle emission or emission without bladder neck closure (retrograde ejaculation). [17] [18] In the series reported by Hartmann and colleagues, patients who had received more than one modality of treatment (such as chemotherapy or radiation therapy and RPLND) had the highest incidence of infertility.[19] Six out of 29 patients who underwent bilateral RPLND in this series suffered from dry ejaculation. A selective RPLND, as described by Donohue and colleagues, results in the sparing of a unilateral sympathetic chain and preservation of antegrade ejaculation.[20] Jacobsen and colleagues reported preserved antegrade ejaculation in 89% of patients undergoing a RPLND after chemotherapy.[21]

Rectal Cancer

Conventional rectal surgery is associated with high rates of impotence and retrograde ejaculation, likely owing to the damage of the pelvic autonomic parasympathetic and sympathetic nerves by blunt dissection. Williams and colleagues described the outcomes of 78 patients who underwent abdominoperineal resection or low anterior resection. Two thirds of patients who underwent abdominoperineal resection had impaired sexual function compared to 30% of patients who underwent low anterior resection.[22] Total mesorectal excision is a standard procedure in rectal cancer surgery. This technique requires sharp dissection of the mesorectum and emphasizes autonomic nerve preservation, resulting in a lower rate of local recurrences and a higher rate of potency preservation. A comparison of sexual outcomes of patients with conventional surgery and mesorectal excision showed that the ability to have intercourse dropped from 75% to 13% in the conventional surgery arm compared to a drop from 67% to 29% in the total mesorectal excision group.[23] Limited information is available about sexual dysfunction in women with rectal cancer. One study reported that 39% of sexually active women and 62% of all women treated for rectal cancer had Female Sexual Function Index scores that were considered abnormal despite the use of nerve-sparing surgery at the reporting institution.[24] Physical factors such as vaginal stenosis, urinary and fecal incontinence, and dyspareunia have a significant impact on female sexual function, and issues such as low libido, decreased vaginal lubrication, and body image concerns also contribute.

Other Surgeries

Gynecologic surgeries can alter sexual function directly by affecting the anatomy of the female genital tract. In a large Swedish study, patients who had been treated with radical hysterectomy were compared to controls matched for age and geographic region. The researchers found no difference in sexual desire or orgasm between the groups. Patients who had been treated with radical hysterectomy reported statistically significant differences in vaginal lubrication, vaginal length, and vaginal elasticity compared with controls.[25] In contrast, a recent publication found that women who had been treated with radical hysterectomy resembled their age- and race-matched peers who have never had a cancer diagnosis or hysterectomy in sexual well-being.[26] While sexual problems occur with considerable frequency in breast cancer patients and often extend beyond the acute phase of treatment, several prospective studies show no difference in quality-of-life outcomes or sexual functioning for breast cancer survivors on the basis of surgical treatment. [27] [28] The use of breast-conserving treatment (versus mastectomy) is not predictive of sexual health after mediating variables are controlled in the analysis.[29]

Radiation Therapy

Radiation therapy affects reproductive function through direct effects on the pituitary, hypothalamus, gonads, uterus, and penile arterial and nerve supplies.

Central Nervous System Effects on Reproductive Function

Mounting evidence suggests that cranial irradiation reduces fertility and sexual function in survivors of childhood cancer. External irradiation to the brain can cause damage to the hypothalamus and impair its function; pituitary cells are more resistant to irradiation. Pituitary dysfunction secondary to irradiation is attributed to disturbance in the hypothalamic-pituitary axis. Hypopituitarism develops slowly after brain irradiation and can be associated with an increase in prolactin levels.[30] The hypothalamic-pituitary function was studied in 31 patients with nasopharyngeal tumors treated with primary radiation therapy (4000 to 6000 cGy).[31] All patients had normal baseline pituitary function. At 1 year from treatment, elevations in thyroid-stimulating hormone and blunted LH response to luteinizing hormone-releasing hormone (LHRH) suggest an abnormality in the pulsatile release of LHRH in males. Three females developed amenorrhea in association with elevated prolactin levels.[31] A dose-dependent response has been suggested, with thyroid-stimulating hormone and gonadotropin abnormalities more commonly seen with brain irradiation doses exceeding 3000 cGy.[32] A recent multicenter study of 593 long-term survivors of acute lymphoblastic leukemia disclosed an increased rate of infertility among children treated with whole-brain radiation.[33] The study suggests that cranial irradiation affects fertility by disrupting gonadotropin secretion. The fertility of female survivors who were treated around the time of menarche was significantly lower than that of sibling controls (rate ratio = 0.59).Fertility in male patients who received cranial radiation doses of 2400 cGy before the age of 9 years was one third that of controls (rate ratio = 0.35). Survivors who were treated at other ages did not have fertility deficits. This suggests a window period in which normal gonadotropin function is most essential for gonadal maturation.[33] This study also shows that reproductive dysfunction can occur at lower doses of brain irradiation (1200 to 2400 cGy) than was previously suggested.

Radiation Effects on Testicular Function

The testis is one of the most radiosensitive tissues; very low doses of radiation cause significant impairment of testis function. Damage may be caused by direct irradiation of the testis or, more commonly, from scattered irradiation during treatment of adjacent targets. Permanent Leydig cell dysfunction occurs with a dose of 2000 to 3000 cGy. Therapeutic irradiation (2400 cGy) to the testes in patients with acute leukemia causes Leydig cell dysfunction, which is manifested by low testosterone levels or a poor testosterone response to gonadotropins. [33] [34] Spermatogenic elements are much more sensitive to radiation than are Leydig cells. Radiation doses as low as 15 cGy transiently suppress spermatogenesis, and doses higher than 600 cGy permanently destroy the germinal elements.[35] Berthelsen evaluated the effects of adjuvant irradiation for seminoma on gonadal function. Retroperitoneal and ipsilateral iliac irradiation resulted in an estimated 200- to 1300-cGy scatter to the unaffected contralateral testicle.[36] Two thirds of patients developed azoospermia, and it took a median of 540 days from the end of treatment before spermatozoa were again found in semen samples. A median of 1250 days passed before the pretreatment sperm count was reached. Sperm counts were low (median: 6 × 106 per ejaculate) up to 5 years after treatment, and serum FSH was elevated (median: 61 IU/L).[36] The time to sperm count recovery is dose dependent at least in the range of 19 to 148 cGy.[37] There is no evidence of an increase in post-treatment congenital abnormalities, and the post-treatment conception rate was 60% to 70%.[36]

Radiation Effects on Ovarian Function

The ovaries of prepubertal children and adolescents, with their greater number of follicles, are relatively resistant to therapy-induced damage. Irradiation that does not involve the pelvis usually does not result in ovarian failure, while individuals who are treated with abdominal, pelvic, or spinal irradiation are at an increased risk of developing ovarian failure, especially if both ovaries are within the field. The effect of radiation on the ovaries is dose-dependent. Recent studies suggest that the LD50 (the radiation dose that is required to kill 50% of oocytes) is less than 2 Gy.[38] The ovaries of younger individuals are less sensitive to damage from radiation than are those of older adults.[39] While a radiation dose of 6 Gy is sufficient to result in permanent ovarian failure in women older than 40 year old, higher doses in the range of 1 to 20 Gy result in permanent ovarian failure in the majority of patients who are treated in childhood.[40]

Pelvic Radiation as a Cause of Reproductive Dysfunction

Radiation therapy is commonly employed as definitive treatment for patients with localized or locally advanced prostate cancer. Although the etiology of erectile dysfunction after definitive radiation therapy for prostate cancer is likely to be multifactorial, mounting evidence suggests that the arteriogenic mechanism is more important in this setting then the cavernosal mechanism. Maintenance of normal erection requires both vasodilation of penile arteries (arteriogenic element) and concomitant relaxation of the corporal smooth muscles (cavernosal element). Duplex ultrasonography can assess arteriogenic function by measuring peak penile blood flow and cavernosal function by measuring distension of the corpora cavernosa in the setting of normal penile flow.[41] Duplex ultrasonography in prostate cancer patients with radiation therapy-induced erectile dysfunction confirmed a 63% rate of arteriogenic dysfunction.[41] This contrasts with prostatectomy-induced erectile dysfunction, in which only 32% had arteriogenic dysfunction while 52% had cavernosal dysfunction.[41] Erectile dysfunction is frequently seen after external beam radiation for prostate cancer and increases in frequency with time. Potency and age prior to treatment are risk factors for erectile dysfunction following completion of therapy. Data from one institution on 802 patients before and after treatment for prostate cancer show that only 15% of patients (24.5% of whom were previously potent) who elected radiation therapy had normal erectile function at a median of 53 months of follow-up.[42] Others have shown higher rates of potency, especially when erectile dysfunction prior to radiation is accounted for. In 290 prostate cancer patients treated with radiation, 62% and 42% of those who were potent before treatment maintained potency at 12 and 24 months, respectively.[43] Potency rates drop further with time. Conformal radiation therapy limits the radiation field while delivering a high dose of radiation to the prostate and may be associated with a lower degree of impotence. [44] [45] Mantz and colleagues described a 5-year potency rate of 53% among 287 prostate cancer patients who were treated with 6000 to 7200 cGy conformal radiation therapy.[45] The use of brachytherapy in the treatment of prostate cancer has also been associated with a lower incidence of impotence. Prostate brachytherapy as monotherapy was associated with 5- and 6-year potency rates of 76% and 52%, respectively, among previously potent patients. [46] [47] The addition of external beam radiation or antiandrogen therapy to brachytherapy decreases the rates of potency substantially. [46] [47]

Pelvic radiotherapy for cervical carcinoma is associated with vaginal atrophy, shortening, or agglutination, making intercourse difficult or impossible for these women.[48] In addition, patients often become menopausal as a result of pelvic radiation. Women who have been treated with pelvic radiation report severe sexual dysfunction despite the fact that their desire for sexual intimacy is similar to that of controls. At 2 years of follow-up, Jensen and colleagues reported 85% of women having no interest in sex, 55% having dyspareunia, and 50% having vaginal shortening. These problems were very significant in comparison to the women's own premorbid sexual function and age-matched controls.[49]

Abdominal and pelvic radiation therapy may be part of therapy for management of Wilms’ tumor, pelvic rhabdomyosarcoma, and Ewing sarcoma of the pelvis or spine. Young patients exposed to flank radiation (20 to 30 Gy) may have preservation of ovarian function. If women do conceive after this degree of abdominal radiation, there is a significant risk of preterm delivery, low-birth-weight infants, and infants that are small for gestational age compared to controls.[50] Other data suggest a particularly high risk of preterm delivery and low birth weight but no congenital malformations in women who conceive within 1 year after completion of irradiation implying uterine or hormonal defects as the cause of these abnormalities.[51]

Hormonal Therapy

Ablative hormonal therapy is often used in patients with androgen- or estrogen-sensitive tumors. The most common applications are prostate cancer and breast cancer.

Gonadotropin-Releasing Hormone Agonists and Antagonists

Leuprolide and goserelin are two potent GnRH analogs that are commercially available in the United States. These two analogs are much more potent in stimulating gonadotropin release than is GnRH. Initial treatment with GnRH agonists results in an LH and FSH surge with resultant gonadal steroid synthesis stimulation. However, after 10 to 14 days of continuous exposure to GnRH analogs, GnRH receptors on gonadotropin cells in the pituitary are downregulated, resulting in inhibition of LH/FSH release and gonadal suppression. Following prolonged GnRH analog therapy, testosterone and estrogen levels are suppressed to castrate levels. In males, this is usually associated with substantial loss of sexual desire and marked decrease in frequency, magnitude, duration, and rigidity of nocturnal erections.[52] Treatment exceeding 2 years results in atrophic testes, which might not recover even if GnRH is discontinued.[53] In females, the use of GnRH in the adjuvant treatment of breast cancer is associated with an increased rate of sexual dysfunction, but the symptoms are usually reversible on discontinuation of therapy.[54]

Antiandrogens

Antiandrogens bind to and block the activity of androgen receptors. Androgen receptor blockage is associated with a rise in FSH/LH and a resultant rise in serum testosterone.[55] Antiandrogens, such as flutamide, bicalutamide, or nilutamide, are commonly used in the management of prostate cancer either with LHRH analogs or following LHRH agonist/antagonist failure. When combined with LHRH analogs, antiandrogens do not add to the incidence of gynecomastia (12% to 13%) or hot flashes (60% to 64%) and do not affect the incidence of impotence, which is universal in these patients.[56] High-dose bicalutamide has been evaluated as monotherapy in patients with advanced prostate cancer. While some studies suggest comparable clinical activity, there is significantly less impotence and loss of libido with antiandrogen monotherapy.[57] Recent reports, however, suggest that the ability to maintain potency while receiving antiandrogen monotherapy is limited. A study evaluating flutamide as monotherapy in 147 previously untreated prostate cancer patients resulted in 22% preservation of sexual activity and 20% preservation of morning erection at 2 to 6 years from start of therapy.[58] The median time to loss of morning erections and sexual activity was 12.9 and 13.7 months, respectively.[58]

Endocrine Therapy and Breast Cancer

Tamoxifen, a selective estrogen receptor modulator, is a commonly prescribed adjuvant hormonal therapy. Tamoxifen has estrogenic effects in bone and endometrium and antiestrogenic effects in breast tissue. This results in an antitumor effect while maintaining bone density. In premenopausal women, the hypothalamus perceives the antiestrogen effect as a state of estrogen deficiency, thus resulting in an increase in LH and FSH and hyperestrogenemia. In postmenopausal women, in whom FSH and LH are elevated and estrogen levels are depressed, tamoxifen reduces gonadotropin secretion.

Treatment with tamoxifen following primary therapy for breast cancer is associated with a high incidence of hot flashes (20% to 50%); less information is available on the incidence of sexual function.[59]Tamoxifen does not make a significant contribution to sexual dysfunction in women greater than age 50,[60] and in a randomized study that examined only premenopausal women, patients receiving tamoxifen alone did not report worse sexual function.[61]

Aromatase inhibitors are increasingly being used as the standard hormonal therapy for postmenopausal women with breast cancer and are successful in increasing distant and overall disease-free survival as well as preventing contralateral breast cancer compared with tamoxifen. Aromatase inhibition results in a marked decrease in estrogen synthesis, leading to minimal levels of circulating estrogen. Aromatase inhibitors such as anastrozole and letrozole are associated with a lower incidence of hot flashes and have been generally better tolerated than tamoxifen. In a recently published report of the quality-of-life measurements of postmenopausal women participating in the ATAC trial (anastrozole [Arimidex] or tamoxifen alone or in combination), patients reported diminished libido (34% versus 26%) and dyspareunia (17% versus 8%) significantly more frequently with anastrozole than with tamoxifen treatment.[62]

Chemotherapy

Effects in Men

Many anticancer drugs, particularly alkylating agents, are gonadotoxic. Though the ultimate assessment of germinal cell function is the attainment of fatherhood, multiple confounding factors exist that make this endpoint difficult to interpret. Therefore, most studies focus on semen analysis and biochemical markers of fertility for practical reasons.

Cyclophosphamide treatment frequently results in testicular dysfunction. In a series of 116 males treated with cyclophosphamide alone, 52 (45%) had evidence of testicular dysfunction.[63] The incidence of gonadal dysfunction increases with the total dose of cyclophosphamide, occurring in over 80% of postpubertal patients receiving more than 300 mg/kg.[64] Cisplatin disrupts spermatogenesis in a dose-dependent fashion. A threshold level of 600 mg/m2 has been identified, above which significant impairment of spermatogenesis is seen.[65]

Combination chemotherapies containing alkylating agents are far more fertility-impairing than are nonalkylating combinations. The majority of men who are treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) become severely oligospermic or azoospermic, and testicular biopsies confirm germinal aplasia. [5] [66] Procarbazine has significant effects on testicular spermatogenesis, and its effects are often irreversible. Non-procarbazine-containing regimens such as cyclophosphamide, vincristine, and prednisone are usually associated with only transient FSH elevations and oligospermia.[67] Chapman and colleagues followed 64 patients with Hodgkin's lymphoma treated with mechlorethamine, vinblastine, procarbazine, and prednisone.[68] Only 4 out of 64 who were treated with the procarbazine-based regimen recovered spermatogenesis after a median follow-up of 51 months.[68] Comparison of the procarbazine-containing regimen MOPP to ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) in patients with Hodgkin's disease revealed a considerably higher azoospermia with MOPP (100%) than in ABVD (35%). Recovery of azoospermia rarely occurred with MOPP and occurred in the majority of patients receiving ABVD.[69] Dose-dependent infertility is clearly evident in Hodgkin's disease patients receiving combination chemotherapy. Azoospermia occurred considerably less often in patients receiving two cycles of MOPP compared to six cycles.[70]

Combination chemotherapy in testicular cancers is associated with FSH elevation and oligospermia. These findings are complicated further by the fact that the majority of testicular cancer patients have abnormal spermatogenesis prior to initiation of therapy. Cisplatin-based regimens are associated with suppression of spermatogenesis following completion of therapy. In 89 patients who were normospermic prior to chemotherapy, the postchemotherapy count was normospermic in 64%, oligospermic in 16%, and azoospermic in 20%. There was clear evidence for recovery beyond 1 year, and the probability of spermatogenesis increased to 48% at 2 years and 80% by 5 years.[71] Testicular cancer patients with pretreatment oligospermia or with persistent FSH elevation at 2 years from treatment are unlikely to recover normal spermatogenesis following treatment.

Effects in Women

Follicular growth and maturation are affected by chemotherapy. Histologic evaluation of ovaries among women who have been treated with cytotoxic chemotherapy show fibrosis and follicular destruction.[72] [73] Premature ovarian failure is a common result of chemotherapy and is dependent on patient age, drug dose, and the duration and type of chemotherapy administered. Alkylating agents are strongly associated with ovarian dysfunction. Daily cyclophosphamide treatment for durations exceeding 1 year are associated with amenorrhea in females younger than 40 years of age. [74] [75] Most series report a 50% or higher incidence of amenorrhea within 1 month of starting cyclophosphamide.[76] Younger females are more tolerant of the effects of chemotherapy and have a better chance of resuming menstruation after completing chemotherapy. In assessing the effects of adjuvant CMF (cyclophosphamide, fluorouracil, and methotrexate) on reproductive function in breast cancer patients, Mehta and colleagues reported a median of 5.5, 2.3, and 1.1 months to onset of amenorrhea in patients younger then 35, 35 to 45, and older than 45 years, respectively.[77] In another study among patients 30 to 40 years of age, a mean dose of 9.3 g of cyclophosphamide was associated with amenorrhea, while patients older than 40 years required a median dose of 5.2 g.[78] A median of 20.4 g was required before the onset of amenorrhea in patients less then 30 years of age.[78] Menses resumed in 50% of those younger than 40 years, while it rarely occurred in females older than 40 years of age.[78] Treatment with the alkylating agent melphalan resulted in amenorrhea in 73% of patients between 40 and 49 years of age compared to 22% in patients younger then 40 years of age.[79] Similar results have been described with other alkylating agents, such as busulfan and chlorambucil. Younger women have a larger number of oocytes in reserve and thus a lesser likelihood of experiencing permanent ovarian damage after alkylating agent chemotherapy in comparison to older females. Other nonalkylating chemotherapies, such as antimetabolites, bleomycin, vinca alkaloids, and daunorubicin, are not a frequent cause of amenorrhea.

Combination chemotherapies have been evaluated more extensively as a cause of premature ovarian failure. Doxorubicin-based regimens in the adjuvant treatment of breast cancer resulted in a 96% frequency of amenorrhea in women 40 to 49 years of age compared to 0% among women 30 years or younger.[80] These regimens frequently incorporated other alkylating agents. Data collected from patients who were treated with MOPP for Hodgkin's disease similarly confirm the importance of age at the time of treatment.[81] Treating lymphoma patients with regimens that do not include procarbazine (e.g., ABVD) results in a lower incidence of premature menopause. [67] [82] The importance of age and chemotherapy intensity has been stressed by a survey of 96 female patients who had been treated with combinations of ifosfamide, methotrexate, cisplatin, etoposide, and doxorubicin for localized osteosarcoma. The study evaluated the incidence of treatment-related amenorrhea and post-treatment fertility.[83] All 24 patients who were treated at a prepubertal age developed menarche at a median age of 13 years. After menarche, 16 had normal menses, and 8 had permanent irregular cycles.[83] Sixty-eight patients (11 to 43 years) were postpubertal on initiation of chemotherapy. Sixty-nine percent of these developed amenorrhea, typically after one cycle of therapy. A four-drug regimen was associated with amenorrhea in 89% of patients, while a three-drug regimen was associated with amenorrhea in only 53%. Amenorrhea was also related to age; 19 of 51 patients younger then 20 years maintained menses through chemotherapy versus only 2 of 17 in patients who were older then 20 at time of treatment. The majority regained menstruation on completion of chemotherapy. Among 22 patients who married after treatment, 20 patients became pregnant at a median age of 27 years. None of the pregnancies resulted in congenital anomalies.[83]

The duration of combination chemotherapy is also of paramount importance in induction of amenorrhea. Treatment of premenopausal women with a combination of cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone resulted in amenorrhea in 55% of patients who were treated for 12 weeks and in 83% of patients who were treated for 36 weeks.[84]

Effects in Children

EFFECTS OF CHEMOTHERAPY ON TESTICULAR FUNCTION IN BOYS.

The prepubertal testes are more resistant to the effects of chemotherapy than are the adult testes. This relative resistance might be due to the nonproliferative status of the prepubertal germinal layer. Although it can take years, a certain degree of spermatogenesis recovery occurs in most boys who receive a total dose of cyclophosphamide of less then 10 g.[85] Gonadal function was assessed in 17 male survivors of childhood sarcomas who were treated with vincristine, actinomycin, and cyclophosphamide with or without doxorubicin.[86] Only two patients who received less than 7.5 g/m2 of cyclophosphamide had normal semen analysis. All patients who received more than 7.5 g/m2 had abnormal semen analysis, and all 5 out of 5 who received more than 25 g/m2 had azoospermia more than 5 years after therapy.[86] Most patients (15 out of 16) maintained a normal testosterone level.[86] MOPP therapy leads to a considerably higher rate of testicular damage, presumably secondary to the added effect of procarbazine. Nine out of 19 prepubertal patients receiving MOPP or cyclophosphamide-based therapy (exceeding 9 g of cyclophosphamide) were sterile at a median of 9 years of follow-up.[87]Pubertal alkylating therapy might be more detrimental to gonadal function than in the prepubertal setting. In a cohort of 12 prepubertal and pubertal patients receiving MOPP therapy, all pubertal patients developed irreversible azoospermia, while two prepubertal patients were able to recover spermatogenesis. Pubertal treatment with MOPP was also associated with a high incidence of gynecomastia in association with low-normal testosterone levels and elevated LH and FSH.[88]

EFFECTS OF CHEMOTHERAPY ON OVARIAN FUNCTION IN GIRLS.

The majority of prepubertal girls and adolescent females who receive standard combination chemotherapy will retain or recover ovarian function during the immediate post-treatment period. Prepubertal ovaries are relatively resistant to the effects of chemotherapy in comparison with postpubertal ovaries. However, histologic examination and ultrasound examination of the ovary following cancer therapy have revealed a decreased number of ovarian follicles compared to age-matched controls.[89] Menopause appears to be triggered when the number of ovarian follicles drops below a threshold, and a reduction in the population of follicles resulting from cancer therapy could result in premature menopause.[90]

Most prepubertal females who received MOPP therapy for Hodgkin's disease achieved normal puberty and were subsequently able to carry normal pregnancies. [91] [92] Treatment of females with acute leukemia with a multidrug regimen of prednisone, vincristine, methotrexate, and 6-mercaptopurine with or without cyclophosphamide resulted in ovarian failure in only one of 17 prepubertal females.[93]Byrne and colleagues evaluated retrospectively fertility rates in childhood and adolescent cancer survivors.[94] In their comparison of 2283 survivors and 3270 siblings controls, there was no apparent effect of alkylating-agent therapy administered alone (relative fertility: 1.02), and only a moderate fertility deficit was evident when alkylating-agent therapy was combined with radiation below the diaphragm (relative fertility: 0.81) among women. The overall relative fertility in women was 0.93, which compared favorably to men's relative fertility of 0.76.[94] Childhood cancer therapy has also been associated with an increased risk of early menopause. In a large cohort of childhood cancer survivors, the principal risks for early menopause were treatment after the onset of puberty, treatment with radiotherapy below the diaphragm, and alkylating agents.[95] Survivors who were diagnosed after puberty and treated with radiation therapy below the diaphragm were 8.5 times more likely to reach menopause in their twenties. The average age for menopause in survivors who were treated with both an alkylating agent and radiation therapy below the diaphragm was 31 years.[95]

High-Dose Chemotherapy (Bone Marrow Transplantation)

Effects in Females

Gonadal dysfunction after high-dose chemotherapy is dependent on age, sex, type of conditioning regimen, and previous therapy. In women, increased age and treatment with an alkylating conditioning regimen including total body irradiation (TBI) result in a high rate of ovarian failure. In 144 women who were transplanted for leukemia after TBI and cyclophosphamide, amenorrhea was present for 3 years following transplantation in all women. Only nine patients eventually recovered their ovarian function.[96] The likelihood of recovering ovarian function decreased by a factor of 0.8 per year of age.[96] TBI enhances the risk of ovarian failure. Ovarian failure usually occurs within 3 months of TBI. A single nonfractionated dose of 10 Gy is likely to result in more damage to the ovary and a lower chance of ovarian recovery than is a fractionated 12-Gy total dose.[96] Recovery of ovarian function is more likely with chemotherapy-only conditioning regimens but is usually limited to females younger than 30 years of age. In a conditioning regimen of cyclophosphamide of 200 mg/kg, all females 26 years of age or younger recovered their ovarian function, while only 5 out of 16 women over age 26 did so.[96] In another report on patients with non-Hodgkin's lymphoma, who were treated with consolidation high-dose chemotherapy (cyclophosphamide, carmustine, and etoposide), 9 out of 56 patients were able to conceive despite receiving a total dose of 10,800 mg/m2 of cyclophosphamide.[97] Pregnancies were limited to females younger then 29 years of age; no birth defects were reported.[97] The addition of busulfan to cyclophosphamide is rarely associated with ovarian recovery, even in younger patients.[98]

Bone marrow transplantation may also be complicated by graft-versus-host disease. When severe, graft-versus-host disease can cause vaginal strictures and adhesions that interfere with intercourse.[99]

Effects in Males

The majority of males transplanted with or without TBI have marked elevations in their LH and FSH. Testosterone levels may be depressed but are usually maintained in the normal range, reflecting adequate compensatory reaction by Leydig cells to the rise in LH. Infertility is the rule in adults and young males receiving high-dose chemotherapy with or without TBI, reflecting the relative sensitivity of the germinal component to chemotherapy and/or radiation therapy relative to Leydig cells. Decreased libido has been reported in bone marrow transplantation patients. This is probably multifactorial and results from psychological stress, mild suppression of testosterone levels, and vascular and neurologic damage. Testosterone levels were found to be in the low normal range in a study of 24 males with features of hypogonadism and erectile dysfunction following transplantation.[100] While supplementation with testosterone resulted in an improvement in libido, there was no clear beneficial effect on erectile dysfunction.[100] Doppler studies in these patient confirmed evidence of cavernosal arterial insufficiency and strongly correlated with prior TBI therapy. [100] [101]

Effects in Children

Permanent ovarian failure is less commonly seen in prepubertal females than in adults. A combination of high-dose chemotherapy and TBI is associated with a higher incidence of ovarian failure than chemotherapy alone. Sarafoglou and colleagues reported a median age of 8.6 years for prepubertal females with acute leukemia treated with bone marrow transplantation (TBI-based regimen) who developed ovarian failure.[102] The median age for prepubertal females who went on to enter puberty was 6.1 years.[102] Even in those who enter puberty, normal uterine maturation is impaired, and the endometrium is atrophic secondary to radiation therapy. Supplementation with hormone replacement improves mucosal thickness, but the total volume of the uterus remains contracted.[103] Long-term follow-up of childhood acute leukemia survivors reveals that TBI is indeed the most important factor in development of gonadal failure. In 77 survivors of leukemia, three groups of treatment were identified: chemotherapy, chemotherapy and cranial irradiation, and chemotherapy and TBI.[104] Forty-four out of 44 patients who were treated with chemotherapy entered and progressed through puberty without sex hormone supplementation. Only one of 18 of patients who were treated with chemotherapy and cranial irradiation developed early amenorrhea accompanied with elevated gonadotropin levels. Eight of 15 patients who were treated with chemotherapy and TBI developed gonadal failure (3 men and 5 women), requiring long-term sex hormone supplementation.[104]

CHEMOTHERAPY AND RADIATION DURING PREGNANCY

Cancer complicates 1 in 1000 pregnancies.[105] The most frequent cancers during pregnancy are cervical cancer, breast cancer, melanoma, ovarian cancer, thyroid cancer, and leukemia.[106] As more women defer childbearing into their thirties and beyond, more cancers are expected to be diagnosed during pregnancy. Chemotherapy has an essential role in the management of many of these tumors. The timing and selection of chemotherapeutic agents should be optimized to maximize the clinical benefit to the patient while minimizing the risk to the fetus ( Box 64-1 ).

Box 64-1 

CHEMOTHERAPY AND RADIATION DURING PREGNANCY

The risk of congenital anomalies is highest for first-trimester exposure and is most commonly associated with antimetabolites such as methotrexate. Decision making should be individualized, and decisions regarding termination or continuation of pregnancy should take into consideration the risks to the mother and the fetus. In first-trimester pregnancies that require initiation of chemotherapy, termination of pregnancy should be considered. In patients who elect to proceed with pregnancy, the choice of chemotherapy should take into account the risks of congenital malformations. Treatment of patients with hematologic malignancies and breast cancer during the second and third trimesters has not been associated with an increased rate of congenital anomalies. A delay in chemotherapy for a few weeks or until delivery for third-trimester pregnancies can be considered if the mother's outcome is unlikely to be compromised. Delivery induction for gestations of more then 32 weeks is another acceptable option for third-trimester pregnancies.

Radiation therapy should be avoided at all stages of pregnancy. First- and second-trimester exposures are associated with congenital abnormalities, and third-trimester exposure can result in cognitive dysfunction.

Fetal Stage of Development and Pregnancy Outcome

The most important factor influencing fetal outcome in cancer patients who are treated during pregnancy is the stage of fetal development on initiation of treatment. The first trimester is the most susceptible period. The blastocyst is relatively resistant to teratogens for the first 2 weeks because it lacks an established circulation. Following implantation but prior to organogenesis, the blastocyst may exhibit damage from chemotherapy resulting in abortion or may survive without manifesting any abnormalities. Organogenesis begins in the fifth gestational week and continues until the eighth week. During organogenesis, the stem cell population is limited, and damage from chemotherapy may result in major defects. Exposure to chemotherapy during the first trimester may result in a malformation rate of 10% to 20% compared to an estimated rate of 3% in the general population.[107] By the thirteenth week of gestation, all organs have developed, with the exception of the brain and gonads.[108] Exposure to chemotherapy on completion of organogenesis (second and third trimesters) is thus unlikely to result in major birth defects but may result in fetal growth retardation. Treatment of patients with hematologic malignancies and breast cancer during the second and third trimesters has not been associated with any increase in the rate of congenital anomalies. [109] [110] [111]

Effects of Different Classes of Chemotherapy on Pregnancy Outcome

Different classes have varying teratogenic potential. Alkylating agents and antimetabolites appear to have a greater potential of causing a detrimental effect than do antitumor antibiotics, platinum analogs, and vinca alkaloids.[112]

Alkylating Agents

Fetal abnormalities have been reported from first-trimester exposure to cyclophosphamide, chlorambucil, and busulfan. [113] [114] [115] [116] [117] No definite causal relationship is available with other agents, such as thiotepa, melphalan, and dacarbazine, but exposure data in the first trimester for these compounds are limited.

Antibiotic Agents

No definite causal relationship with congenital malformations has been documented with dactinomycin or bleomycin. There have been reports of normal children born to patients exposed during the first, second, and third trimesters.

Antimetabolites

Methotrexate is known for its teratogenic effects and has been used as an abortifacient. Congenital anomalies have been described with first-trimester use. Malformations include severe skull abnormalities, heart defects such as dextroposition, and digital anomalies. [118] [119] Exposure starting as late as 11 weeks has been associated with anomalies.[119] 5-Fluorouracil may be similarly associated with congenital anomalies when administered in the first trimester. One case of multiple congenital anomalies including radial dysplasia, absent digits, and hypoplasia of multiple organs has been reported in a first-trimester exposure.[120] Cytarabine has been commonly used in second- and third-trimester pregnancies in hematologic malignancies without a reported increase in congenital defects. First-trimester exposure has been associated with congenital abnormalities, including microtis and auditory canal atresia, lobster claw hand and other digital anomalies, and lower-extremity defects. [121] [122] Other studies have reported normal pregnancy outcome in first-trimester exposures.[123] There is currently no information on pregnancy outcomes in patients who have been treated with the newer antimetabolite gemcitabine.

Anthracyclines

First-trimester exposures have been associated with normal and abnormal fetal outcomes. Imperforate anus, rectovaginal fistula, and microcephaly have been described following first-trimester exposure to doxorubicin.[124]

Vinca Alkaloids

Definite fetal anomalies secondary to vinca alkaloids have not been reported. Sporadic anomalies have been reported in patients receiving combination therapy. Several pregnancies with exposure to vinca alkaloids during the first trimester of pregnancy have resulted in normal neonates. [107] [125]

Platinum Analogs

Ten pregnant women with cancer have been reported who received cisplatin during the second or third trimester.[126] None of the neonates demonstrated any congenital anomalies, but fetal growth was restricted in 50% of pregnancies.

Taxanes

Limited information is available on the clinical effects of taxanes on pregnancy. There has been one report of an ovarian cancer patient treated during the third trimester of pregnancy with carboplatin and paclitaxel without any adverse events in the newborn.[127] Treatment of a case of metastatic breast cancer with docetaxel during the second and third trimesters of pregnancy resulted in a normal healthy newborn.[128]

Topoisomerase II Inhibitors

Etoposide has not been reported to cause congenital malformations. However, fetal marrow suppression manifesting as severe neonatal anemia and leukopenia has been reported in a patient treated for leukemia.[129]

In general, chemotherapy has not been associated with an increased risk of congenital malformations if administered in the second or third trimesters, but an increased incidence of growth restriction and premature birth has been noted. An increased risk of congenital anomalies has been associated with treatment in the first trimester. Doll and colleagues reported a 15% incidence of fetal malformations in association with first-trimester chemotherapy exposure versus 1.3% for second- and third-trimester exposures.[130] This risk is apparently highest for antimetabolites, especially methotrexate. If cancer occurs in the first trimester and systemic cytotoxic therapy is clearly indicated, termination of the pregnancy should be considered. Delay in chemotherapy until it can be given more safely in the second and third trimesters should be considered if the outcome for the mother is not at risk. The long-term effects on progeny have not been adequately evaluated for different chemotherapeutic agents. Anecdotal data suggest that most offspring who are exposed in utero exhibit normal physical and mental development. Eighty-four children who were born to patients with hematologic malignancies and were exposed to chemotherapeutic agents in utero were followed for a median of 18.7 years.[131] In all the children who were studied, the learning and educational performances were normal, and no congenital, neurologic, or psychological abnormalities were observed. There was no apparent increase in malignancies. Some of these individuals became parents during the period of follow-up. Twelve second-generation offspring were evaluated, and all of them were normal.[131]

Targeted Therapy

Several newer agents have been developed to target specific growth receptor, antigens, or kinases that are essential for cell growth and development. Two commercially available agents are the anti-Her2/neu antibody trastuzumab and the anti-CD-20 antibody rituximab. Reproductive data in monkeys using 25 times the human equivalent of trastuzumab did not show any evidence of teratogenicity. However, trastuzumab diffuses through the placental circulation, and acute or long-term effects on human progeny have not been evaluated. Rituximab has not been evaluated extensively in reproductive animal models. A 29-year-old patient with diffuse large cell lymphoma was treated during her second and third weeks of pregnancy with a combination of rituximab and CHOP therapy.[132] She delivered a healthy female newborn at 36 weeks.

Imatinib is now a standard therapy for patients with chronic myeloid leukemia. A series of 19 pregnancies involving 18 patients (10 females and 8 males) who conceived while receiving imatinib for the treatment of chronic myeloid leukemia was recently reported. All female patients discontinued therapy immediately on recognition of pregnancy. There were three spontaneous abortions, including two of the ten pregnancies in female patients. In addition, two (13%) of the 16 babies who were born from these parents had congenital abnormalities (one baby with hypospadias, one with mild rotation of the small intestine). Given the constraints of the small series, this could represent a higher-than-expected frequency of congenital abnormalities. At present, the recommendation is for patients on imatinib to practice effective barrier forms of birth control and to discontinue imatinib if pregnant or lactating.[133]

Immunomodulators

Limited data are available on the effects of interferons and interleukins on pregnancy. In animals, interferon-α and interleukin-2 have abortifacient and embryolethal effects. More than 20 case reports of pregnancy during interferon-α treatment in all three trimesters have been reported. [134] [135] [136] None of the cases were associated with congenital anomalies, but growth retardation and premature births were more frequent than expected.[136]

Effects of Radiation Therapy on Pregnancy Outcome

Human data regarding the effects of radiation on fetal outcome is limited to accidental exposure and to nuclear disaster victims. Similar to chemotherapy, the effects seem to be most pronounced during the period of organogenesis. During the period of 8 to 25 weeks of pregnancy, the central nervous system is particularly sensitive to the effects of radiation. The most comprehensive review of clinical effects of pelvic radiation therapy was reported by Dekaban.[137] Pelvic irradiation up to 3 weeks following conception did not result in severe congenital anomalies, although a considerable number of embryos may have been resorbed or aborted.[137] Irradiation between weeks 4 and 11 led to the development of severe congenital anomalies in many organs. Exposure between weeks 11 and 16 led to anomalies of the eye, skeleton, and genital organs; stunted growth; microcephaly; and mental retardation.[137] Exposure between 16 to 20 weeks was associated with mild microcephaly, mental retardation, and stunted growth. Later exposures were unlikely to cause structural abnormalities.[137]

Data from survivors of the atomic bombs in Hiroshima and Nagasaki suggest a dose-dependent effect of radiation on congenital anomalies, a dose of 50 cGy resulting in a 40% risk of microcephaly. Doses in excess of 10 cGy may result in cognitive impairment, and higher exposures result in further exacerbation of mental retardation. In utero radiation exposure also results in an increased risk of carcinogenesis with an estimated 6% risk of cancer by age 15 per Gy of exposure.[138]

Radiation therapy should be avoided during pregnancy because of the significant physical, functional, and mental dysfunction that can result from exposure in the first and second trimesters. Even in cases such as breast cancer, in which breast irradiation is given with abdominal shielding, the estimated fetal exposure with 5000 cGy to the primary tumor is 14 to 18 cGy. This is well above the proposed threshold for microcephaly and mental retardation.[139]

PREVENTION

Modifying the treatment and its timing as discussed previously may reduce reproductive complications, but care must be taken not to compromise treatment efficacy, and detailed discussions with patients are mandatory ( Box 64-2 ).

Box 64-2 

PREVENTION AND TREATMENT OF SEXUAL AND REPRODUCTIVE DYSFUNCTION OF CANCER THERAPY

Prevention

The best prevention is the selection of equally effective treatments but with lower toxicities. Treatment of Hodgkin's disease with ABVD rather than MOPP will often result in fertility preservation. Bone marrow-conditioning regimens that do not incorporate total body radiation should be considered in bone marrow transplant patients. Ovarian and testicular suppression with GnRH analogs has not been shown conclusively to protect gonadal function and should be limited to clinical studies.

All males who are contemplating future fatherhood and for whom either chemotherapy that has been associated with infertility (such as alkylating agents) or pelvic radiation is planned should be offered sperm banking. Oocyte banking and ovarian cryopreservation continue to be investigated in females and have not yet been standardized. In vitro fertilization with embryo cryopreservation may represent another alternative for females who are undergoing gonadal-toxic treatments.

Treatment

Treatment involves hormonal replacement for patients with premature ovarian failure and low testosterone levels. Estrogen replacement ameliorates menopausal symptoms, including hot flashes, vaginal dryness, and dyspareunia. Vaginal-directed estrogen therapy can improve local vaginal symptoms in patients with relative contraindications to systemic estrogen replacement. For patients with a history of breast cancer, nonhormonal vaginal moisturizers and lubricants remain the first line of therapy.

Testosterone replacement in men improves the libido and reduces hot flashes and can improve potency in severe androgen deficiency cases. Impotence secondary to surgery or radiation therapy may be successfully treated with sildenafil. This agent should be avoided in patients with significant cardiovascular illness and is contraindicated in patients who are receiving nitrates. Sildenafil therapy should be considered as a first-line pharmacologic therapy in impotent patients with normal testosterone levels and in whom psychosocial etiologies are not suspected.

Assisted reproductive technologies such as intrauterine insemination, in vitro fertilization, and ICSI should be considered as options for restoring fertility in couples who have difficulty conceiving after cancer therapy.

Retroperitoneal nerve-sparing dissections result in significant improvements in potency rates after radical prostatectomy. Similar results are reported in rectal surgeries with nerve-sparing dissection. Alternative chemotherapeutic regimens with low gonadal toxicity potential should be considered when possible. The substitution of ABVD therapy has resulted in similar or better efficacy in the treatment of Hodgkin's lymphoma and a lower rate of ovarian and testicular failure.

Unfortunately, most cancer diagnoses have limited options of treatment, and the choice of a regimen with a low potential for gonadal toxicity is often not feasible. Spermatogenesis and follicular growth and maturation are particularly sensitive to the effects of chemotherapy because of their high mitotic rate. Thus, treatment interventions that suppress germinal function during administration of cytotoxic therapy may limit the gonadal toxicity. GnRH analogs have been shown to inhibit spermatogenesis in various animals and in humans. The use of GnRH analogs has been reported to protect rat testes from chemotherapy and radiation. [140] [141] However, treatment of testicular cancer and Hodgkin's disease patients with LHRH analogs has failed to show any protective effects against the development of azoospermia. [142] [143] [144] Effective inhibition of spermatogenesis may require several weeks of hormonal manipulation with GnRH analogs. Treatment with GnRH analogs for several weeks prior to initiation of chemotherapy is often not feasible clinically and may account for the failure of previous studies to show a protective effect on gonadal function.

Similar attempts to protect the ovaries from cytotoxic chemotherapy by suppressing cycling through GnRH analogs and oral contraceptives have been made. A small study of patients with Hodgkin's disease receiving alkylating agent-based chemotherapy and oral contraceptives showed that five of six patients resumed normal menstrual function at 26 months.[145] Other studies of oral contraceptives and GnRH analogs failed to show any protective effects in patients with Hodgkin's disease in comparison with controls. [143] [146] However, one prospective study in patients with lymphoma showed a significant protection against ovarian failure with cotreatment with GnRH analogs.[147] Eighteen patients with lymphoma were treated with a monthly injection of depot GnRH agonist starting prior to chemotherapy and continuing for a maximum of 6 months. Most of these patients (15 of 18) were treated with the MOPP/ABVD combination chemotherapy followed by mantle field irradiation in 10 patients. This group of prospectively treated lymphoma patients was compared to a matched control group of 18 women. Only 39% of the patients receiving chemotherapy alone resumed spontaneous ovulation in comparison with 94% of those receiving GnRH analogs along with chemotherapy. [147] [148]

Other means of protection from radiation effects include gonadal shielding. In females receiving pelvic radiation, transposition of the ovaries might be one alternative to avoid radiation damage. Transposition of one or two ovaries can be done at the time of laparotomy or laparoscopically. Spontaneous pregnancy rates after ovarian transposition are low, presumably because of the distorted tubo-ovarian anatomy secondary to the procedure itself or the local therapy (radiation) to the pelvic area.[149]

TREATMENT

Treatment of reproductive complications aims at relieving the symptoms related to gonadal failure and providing assistance in achieving reproduction. This section focuses on hormone replacement, treatment measures for impotence, and reproductive assistance technologies.

Hormonal Replacement

Premature ovarian failure results in the sudden onset of menopausal symptoms secondary to an abrupt decrease in estrogen levels. Sexual symptoms related to ovarian failure include vaginal atrophy, thinning of vulvar tissue and the vagina, decreased vaginal lubrication and elasticity, mood swings and irritability, and hot flashes. Estrogen replacement therapy (in combination with progesterone in patients without hysterectomy) can reverse most of these symptoms and should be discussed with all patients with iatrogenic ovarian failure. Risks, including increased rate of cardiovascular and cerebral accidents, and benefits such as osteoporosis prevention should be addressed prior to initiation of therapy.[150] Hormonal replacement therapy in breast cancer patients continues to be an area of concern because of the theoretical potential of promoting tumor growth. However, no reports have yet shown a detrimental effect of estrogen replacement in this cancer population. Patients who are not candidates can be treated symptomatically with vaginal moisturizers (e.g., Replens) and water-based lubricants (e.g., K-Y liquid). Vaginal-directed estrogen therapy with an Estring vaginal ring, estrogen creams, or Vagifem tablets have also resulted in improvements in symptoms of vaginal dryness and dyspareunia and a decrease in the incidence of urinary tract infections.

Male hypogonadism secondary to chemotherapy and radiation therapy is associated with loss of libido, hot flashes, and impotence. Testosterone replacement as a depot injection or in a transdermal formulation may restore sexual function in those instances. [151] [152]

Management of Erectile Dysfunction

The advent of sildenafil citrate (Viagra) marks an important milestone in the treatment of male impotence. The physiologic mechanism of penile erection involves the release of nitrous oxide in the corpus cavernosum during sexual stimulation. Nitrous oxide results in an increase in cyclic guanosine monophosphate, which in turn results in corpus cavernosum smooth muscle relaxation and allows an increase in blood flow. Sildenafil improves the ability to achieve and maintain an erection by blocking the degradation of cyclic guanosine monophosphate.

Sildenafil leads to successful intercourse in prostate cancer patients with erectile dysfunction after prostatectomy, external beam radiation, or brachytherapy. Response rates typically range between 70% and 80%. [153] [154] [155] [156] The ease of oral administration and the efficacy of this agent have made it the most commonly prescribed agent for erectile dysfunction.[157] Because sildenafil potentiates the hypotensive effects of nitrates, prescribers should ensure that patients taking sildenafil do not have any significant cardiac history and are not receiving any concomitant nitrate medications. Alternative therapies include penile injections, vacuum devices, or intraurethral suppositories. These are more cumbersome to the patient and are associated with high dropout rates.[158] In refractory situations, surgical intervention with penile implants may be considered.

Assisted Reproductive Technologies

Once germinal testicular aplasia or premature ovarian failure occurs secondary to cancer therapy, the damage might be irreversible. Unless sperm or embryonic banking is performed prior to treatment, these patients will not be able to parent their own biological children. This issue has not been given adequate attention, and its importance to patients has long been overlooked. A survey of 904 men diagnosed with cancer revealed that 51% of men wanted children in the future.[159] Only 60% of men recalled being informed about infertility, and only 51% had been offered sperm banking.[159] Lack of prior discussion about sperm banking with patients was the most common reason for failing to bank sperm.[159]

Several advances in reproductive technologies allow for fertility preservation in patients who are undergoing gonadal toxic therapies. Intrauterine insemination is accomplished by selecting washed sperm with high motility and injecting them directly into the uterus at the time of ovulation. This procedure requires cryopreservation of 5 to 10 million normal sperm. In vitro fertilization with embryo transfer involves culturing the aspirated oocytes and spermatozoa in vitro, followed by the transcervical replacement of the embryo into the uterine cavity. With in vitro fertilization with embryo transfer, the number of sperm required is 0.5 to 1 million.[160] Intracytoplasmic sperm injection (ICSI) involves the injection of a single sperm into the cytoplasm of the oocyte with transcervical placement of the embryo into the uterine cavity. ICSI reduces the criteria for sperm cryopreservation theoretically to the presence of one motile sperm. This makes almost any male cancer patient who is not completely azoospermic a candidate for sperm cryopreservation. Even in patients with complete ejaculatory azoospermia, testicular sperm extraction followed by ICSI and embryo cryopreservation might represent an option for fertility preservation. [161] [162] Testicular sperm extraction is typically achieved by obtaining open biopsies of testicular tissues with or without microdissection.[163] ICSI is now performed in 60% to 80% of assisted reproductive procedures in some metropolitan U.S. areas and is the procedure of choice for couples with a male infertility factor. In patients for whom sperm is stored or extracted successfully, successful pregnancy rates in the range of 30% are expected. [162] [164] Transrectal electroejaculation is yet another viable method for sperm collection for the purpose of cryopreservation or in vitro fertilization in patients with retrograde ejaculation.[165] Other options of sperm collection in patients with retrograde ejaculation are insemination by using sperm-rich urine (after masturbation) or bladder washings. Successful reports of insemination by using these collection methods have been reported, using techniques ranging from intrauterine insemination to ICSI.[166]

Oocyte cryopreservation has been associated with few pregnancies. Low pregnancy yield as well as the need to delay chemotherapy to achieve appropriate follicular stimulation limits the use of this technique for female fertility preservation. Ovarian tissue cryopreservation is a novel technique that is under investigation. The procedure involves oophorectomy and cryopreservation prior to the initiation of cancer treatments. On completion of cancer-directed therapy and when conception is planned, the frozen banked ovarian tissue is thawed and autotransplanted in the patient. Successful ovulation after autotransplantation has been reported, and the procedure continues to be under investigation.[167] Another option for fertility preservation involves in vitro fertilization and embryo cryopreservation prior to initiation of treatment. The technique is cumbersome and expensive, can delay the initiation of effective chemotherapy, and constitutes an ethical dilemma.

For patients who are unable to conceive secondary to uterine or cervical abnormalities attributed to the cancer or its treatment, in vitro fertilization with implantation in a surrogate has been described.[168]

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