Central Nervous System Effects on Reproductive Function

Pituitary dysfunction as a result of irradiation is attributed to a disturbance in the hypothalamic-pituitary axis. In both men and women, it has been shown that cranial irradiation of 35 to 40 Gy or greater disturbs the hypothalamic-pituitary axis and increases the risk of infertility.³² A study of 593 long-term survivors of childhood acute lymphoblastic leukemia disclosed an increased rate of infertility among those treated with whole-brain radiation.³³

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. 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.34,35 Radiation doses as low as 15 cGy transiently suppress spermatogenesis, and doses higher than 600 cGy permanently destroy the germinal elements.³⁵ Berthelsen³⁶ 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. Azoospermia developed in two thirds of patients, 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). No evidence of an increase in posttreatment congenital abnormalities was found, and the posttreatment conception rate was 60% to 70%.

Radiation Effects on Ovarian Function

Human oocytes are sensitive to the effects of radiation, and it has been suggested by Wallace et al.³⁷ that the LD₅₀ (the radiation dose that is required to kill 50% of oocytes) is less than 2 Gy. In a review of the risk of premature menopause because of cancer treatment, it was found that younger ovaries are less sensitive to the effects of irradiation. Although a radiation dose of 6 Gy is sufficient to result in permanent ovarian failure in women older than 40 years, higher doses in the range of 10 to 20 Gy result in permanent ovarian failure in the majority of patients who are treated in childhood.³⁸

Pelvic Radiation as a Cause of Reproductive Dysfunction

Radiation therapy is commonly used 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, the arteriogenic mechanism appears to be more significant than 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.³⁹ In patients with prostate cancer who have radiation therapy–induced erectile dysfunction, duplex ultrasonography confirmed a 63% rate of arteriogenic dysfunction. By contrast, with prostatectomy-induced erectile dysfunction, only 32% of patients had arteriogenic dysfunction and 52% had cavernosal dysfunction.³⁹ Erectile dysfunction is frequently seen after external beam radiation for prostate cancer and increases in frequency with time. In 290 patients with prostate cancer who were treated with radiation, 62% and 41% of those who were potent before treatment maintained potency at 12 and 24 months, respectively, and potency rates dropped further with time.⁴⁰ 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.^41,42 Mantz and colleagues⁴² described a 5-year potency rate of 53% among 287 patients with prostate cancer who were treated with 6000 to 7200 cGy conformal radiation therapy.⁴² 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. Furthermore, the addition of external beam radiation or antiandrogen therapy to brachytherapy decreases the rates of potency substantially.^43,44 The use of intensity-modulated radiation therapy for nonmetastatic prostate cancer has increased significantly in the past decade, and although patients receiving this therapy are less likely than those receiving conformal radiation therapy to undergo additional cancer treatments, there is an increased association with erectile dysfunction ^45.

Pelvic radiotherapy for cervical carcinoma is associated with vaginal atrophy, shortening, or agglutination, making intercourse difficult or impossible for women who receive this therapy.⁴⁶ At 2 years of follow-up, Jensen and colleagues⁴⁷ reported that 85% of women had no interest in sex, 55% had dyspareunia, and 50% had vaginal shortening. These problems were very significant in comparison with the women’s own premorbid sexual function and age-matched control subjects.

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. Women who do conceive after treatment with this degree of abdominal radiation have a significant risk of preterm delivery, low birth weight infants, and infants who are small for gestational age compared with control subjects.⁴⁸ Other data also found 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. These data imply that uterine or hormonal defects are the cause of these abnormalities.⁴⁹

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. After prolonged GnRH analog therapy, testosterone and estrogen levels are suppressed to castrate levels. In men, this is usually associated with substantial loss of sexual desire and a marked decrease in frequency, magnitude, duration, and rigidity of nocturnal erections.⁵⁰ Treatment for longer than 2 years results in atrophic testes, which might not recover even if GnRH is discontinued.⁵¹ In women, 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 upon discontinuation of therapy.⁵²

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.⁵³ Antiandrogens, such as flutamide, bicalutamide, or nilutamide, are commonly used in the management of prostate cancer either with luteinizing hormone-releasing hormone (LHRH) analogs or after LHRH agonist/antagonist failure. A recent prospective study combining flutamide and leuprolide demonstrated a decrease in libido, sexual activity, and perceptions of masculinity during therapy.⁵⁴ Once therapy ended, these levels improved during a 2-year period, although not to baseline levels. Erectile function, however, did return to baseline. High-dose bicalutamide has been evaluated as monotherapy in patients with advanced prostate cancer. Although some studies suggest comparable clinical activity, significantly less impotence and loss of libido occur with antiandrogen monotherapy.⁵⁵ The ability to maintain potency while receiving antiandrogen monotherapy is limited. A study evaluating flutamide as monotherapy in 147 previously untreated patients with prostate cancer resulted in 22% preservation of sexual activity and 20% preservation of morning erection at 2 to 6 years from the start of therapy.⁵⁶ The median time to loss of morning erections and sexual activity was 12.9 and 13.7 months, respectively.

Endocrine Therapy and Breast Cancer

Tamoxifen, a selective estrogen receptor modulator, is a commonly prescribed adjuvant hormonal therapy. In premenopausal women, the hypothalamus perceives the antiestrogen effect as a state of estrogen deficiency. This results 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.

In a randomized study of standard (n = 45) versus high-dose (n = 53) tamoxifen, patients experienced hot flashes (85%), vaginal dryness and/or dyspareunia (47%), and decreased sexual desire (44%).⁵⁷ Decreased sexual interest correlated significantly with vaginal dryness and/or dyspareunia. These symptoms decreased significantly after discontinuation of tamoxifen. Other reports have shown that tamoxifen does not make a significant contribution to sexual dysfunction in women older than 50 years,⁵⁸ and in a randomized study that examined only premenopausal women, patients receiving tamoxifen alone did not report decreased sexual function.⁵⁹

Aromatase inhibitors are increasingly 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. In a recently published report of the quality-of-life measurements of postmenopausal women participating in the “Arimidex, Tamoxifen, Alone or in Combination” (ATAC) trial, patients reported diminished libido (34% vs. 26%) and dyspareunia (17% vs. 8%) significantly more frequently with anastrozole (Arimidex) treatment than with tamoxifen treatment.⁶⁰

Effects in Women

Follicular growth and maturation are affected by chemotherapy through adverse effects on DNA function and prevention of cell division within ovarian cells. The risk of infertility is dependent on patient age, drug dose, and the duration and type of chemotherapy administered. Histologic evaluation of ovaries among women who have been treated with cytotoxic chemotherapy shows fibrosis and follicular destruction.68,69 Table 60-2 summarizes the risk of amenorrhea from commonly used cancer therapy regimens. Alkylating agents are strongly associated with ovarian dysfunction.^70,71 Most series report a 50% or higher incidence of amenorrhea within 1 month of starting cyclophosphamide.⁷² Younger women are more tolerant of the effects of chemotherapy and have a better chance of resuming menstruation after completing chemotherapy.⁷³ In one study among patients 30 to 40 years of age, a mean dose of 9.3 g of cyclophosphamide was associated with amenorrhea, whereas patients older than 40 years required a median dose of 5.2 g.⁷⁴ A median of 20.4 g was required before the onset of amenorrhea in patients younger than 30 years.⁷⁵ Menses resumed in 50% of patients younger than 40 years, and it rarely occurred in women older than 40 years.⁷⁶ Other nonalkylating chemotherapies, such as antimetabolites, bleomycin, vinca alkaloids, and daunorubicin, are not a frequent cause of amenorrhea.