Reproductive Complications

Summary of Key Points

Reproductive complications resulting from cancer or its treatment are expected to increase as the number of cancer survivors increases.
The risks of infertility related to cancer therapy and the available fertility preservation options should be discussed with all patients of reproductive age before cancer therapy begins.
Oligospermia is present in more than 50% of patients with Hodgkin lymphoma and testicular cancer.
Prostatectomy and other pelvic and rectal surgeries are associated with erectile dysfunction; retroperitoneal dissection is associated with retrograde ejaculation.
Cranial irradiation of 35 to 40 Gy or greater increases the risk of infertility in men and women.
The use of phosphodiesterase-5 inhibitors has reestablished potency in a large number of patients with surgery- or radiation-induced erectile dysfunction.
Radiation can affect testicular spermatogenesis after doses as low as 15 cGy. Ovarian function is more resistant, but the effects are age related.
Gonadal shielding and ovarian transposition ameliorate the effects of radiation on gonadal function.
Gynecologic surgery can have a direct impact on sexual function by altering the normal female genital anatomy.
Alkylating agents are associated with the highest rates of infertility in men and women.
Dose, duration, and choice of chemotherapy agents are directly associated with the risk of infertility.
Antimüllerian hormone levels are useful markers of ovarian reserve. The return of menses does not indicate preservation of ovarian function.
Recent data suggest that administration of goserelin with chemotherapy may protect against ovarian failure in women with hormone receptor–negative breast cancer.
Patients receiving long-term endocrine treatment may be reluctant to disclose sexual dysfunction or infertility concerns. Sensitive and direct questioning is often needed.

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

Patients with cancer often experience acute and long-term complications related to cancer and its treatment. Insults to reproductive health constitute an often overlooked dimension of cancer treatment. 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 critical to the overall success of cancer therapy. This chapter focuses on the reproductive complications of cancer and its treatment that play a central role in the quality of life of patients with cancer.

Reproductive Physiology

Gonadal Form and Function

The ovary produces mature fertilizable eggs, sex steroids, and reproductive and gonadal peptides. These activities are carried out in an integrated manner within the follicle. Humans have approximately 1 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. Spermatogenesis occurs in Sertoli cells within the seminiferous tubules. 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.

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. 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. The gonadal proteins activin, inhibin, and follistatin also modulate the release of FSH. 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. Activation of gonadotropin receptors on the plasma membranes of Leydig cells and granulosa and theca cells induces the regulation and production of testosterone and of female steroid hormone production and follicular maturation, respectively.

Direct Effects of Cancer on Reproductive Function

Recent studies have explored the direct effects of malignancy on fertility. Suboptimal fertility in patients with cancer may result from malnutrition related to deficiencies in vitamins, minerals, and trace elements required for optimal spermatogenesis. Tumor-associated cytokines including interleukins, tumor necrosis factor, and other tumor secreting substances as well the host's innate response to the cancer can adversely affect spermatozoa function, leading to decreased sperm motility. Poor semen quality has been characterized in treatment-naïve patients with cancer, but the etiology is not entirely understood. Numerous factors likely contribute, including preexisting defects in germ cells, local tumor effects, autoimmune and systemic effects, and cancer-associated endocrinopathies.

In patients diagnosed with prostate cancer, one-third to one-half of men already have sexual dysfunction at the time of diagnosis. Prevalence of infertility and sexual dysfunction increases with aging and comorbid disease. Sexual dysfunction in men diagnosed with prostate cancer was significantly worse than in healthy controls in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial in the United States ( P < .001), and the effects persisted across 10 years of follow-up.

Gonadal tumors can result in reproductive dysfunction as a result of gonadal germinal tissue destruction and 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 as a result of pain. Women with invasive vulvar and vaginal cancers and advanced cervical cancers often have symptoms of postcoital bleeding or dyspareunia. Men with testicular cancer may have diffuse testicular pain, swelling, and tenderness that interfere with intercourse. Penile cancer usually has presenting symptoms of 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 with amenorrhea and galactorrhea in women. Other pituitary adenomas can affect reproductive function by destroying LH- and FSH-producing gonadotropes. Metastatic disease that affects the hypothalamus-pituitary axis also leads to reproductive dysfunction. Paraneoplastic syndromes are an infrequent but well-documented cause of reproductive dysfunction.

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

Although men with Hodgkin lymphoma may have pretreatment impairment of spermatogenesis, no well-defined predictors of semen quality at the time of diagnosis have been identified. Temperatures greater than 38.5°C have been shown to adversely affect sperm analysis in patients before treatment of Hodgkin lymphoma. Some studies have indicated a correlation between elevated erythrocyte sedimentation rate and semen quality. In other studies, no correlation has been found between semen abnormalities and disease stage or systemic symptoms. An evaluation of patients with early-stage Hodgkin lymphoma reported that 90% had good or intermediate sperm quality. In this study of 474 patients, no relationship was found between sperm quality and age, clinical stage, or smoking. However, B symptoms (fever, weight loss, and night sweats) had a statistically negative effect on sperm quality, especially fever and night sweats. No association has been found between sperm quality and pretreatment FSH levels.

The association between testicular cancer and abnormalities of spermatogenesis is even more pronounced. Several cancer subtypes have been shown to decrease sperm counts, with testicular cancer having some of the worst pretreatment sperm counts in numerous studies. 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 study found that total sperm count was lower in men with testicular germ cell cancer (median, 29 × 10 ⁶ /mL versus 162 × 10 ⁶ /mL) than in healthy men. Another study evaluating pretreatment semen parameters in men with cancer found that 45% of men with testicular cancer were in the subfertile range, compared with 16% of men with all other known cancers and 10% of men without cancer undergoing elective vasectomy. Overall, men with testicular cancer had sperm concentrations that were significantly lower than those in men with other malignancies. Histologic investigations have revealed a high prevalence of dysfunctional spermatogenesis even in the contralateral testicle that is uninvolved with cancer. An increased risk of testicular cancer has also been observed in men with an abnormal semen analysis and infertility. Infertile men with abnormal semen analyses have a 20-fold higher incidence of testicular cancer compared with the general population. 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 treatments include radical prostatectomy, radical cystectomy, rectal cancer surgery, orchiectomy and retroperitoneal dissection, and radical hysterectomy.

Prostate Cancer

Prostatectomy results in obstructive infertility in 100% of cases. The options for patients are restricted to assisted procreation techniques if a cryopreservation of sperm was not done before prostatectomy. Erectile dysfunction in patients undergoing radical prostatectomy commonly occurs after surgery. Steineck and colleagues randomly assigned 376 patients to radical prostatectomy versus watchful waiting; the incidence of erectile dysfunction was significantly higher in the surgical group (80%) compared with the observation group (45%). Bilateral nerve-sparing surgeries are considerably more effective in allowing the patient to maintain an erection compared with unilateral nerve-sparing surgeries. Potency rates after bilateral sparing surgery at 3 years were 76% compared with 30% with unilateral nerve-sparing surgery in previously potent patients younger than 60 years. The rates of potency are lower in older patients and in patients with known erectile dysfunction before surgery. A recent study also indicated that incontinence and sexual dysfunction remain high with robotic-assisted laparoscopic radical prostatectomy; patients should not expect fewer adverse effects with this newer method. Orgasmic disturbances after radical prostatectomy include altered perception of orgasm, anorgasmia, and orgasm-associated pain. Prevalence rates vary widely among studies, but symptoms decrease over time.

Testicular Cancer

Orchiectomy results in the loss of gonadal tissue and subsequent decreased sperm production. Petersen and colleagues reported a reduction in sperm concentration in 30 of 35 men undergoing unilateral orchiectomy, with 3 of 35 developing new-onset azoospermia. Herr and colleagues demonstrated that fertility remains a possibility after orchiectomy, with a reported paternity rate of 65% among men having undergone unilateral orchiectomy for stage I testicular cancer. Retroperitoneal lymph node dissection (RPLND) frequently damages the sympathetic nerves that innervate the seminal vesicles and the bladder neck, which leads to loss of seminal vesicle emission or emission without bladder neck closure (retrograde ejaculation). In a recent report on long-term survivors of testicular cancer, when comparing different treatment modalities, only RPLND was associated with sexual dysfunction related to ejaculatory dysfunction. The risk for retrograde or complete loss of ejaculation varies depending on the surgical procedure. A selective RPLND, as described by Donohue and colleagues, results in the sparing of a unilateral sympathetic chain and preservation of antegrade ejaculation. Jacobsen and colleagues reported preserved antegrade ejaculation in 89% of patients undergoing an RPLND after chemotherapy. Pettus and colleagues reported similar findings in a study of 341 patients undergoing postchemotherapy RPLND. Postoperative antegrade ejaculation was reported by 107 of 136 (79%) patients, with nerve-sparing techniques performed in 40% of patients.

Rectal Cancer

Despite improved outcome in rectal cancer treatment, complications and long-term consequences of sexual and reproductive dysfunction plague management of rectal cancer. Conventional rectal surgery is associated with high rates of impotence and absent, retrograde, or painful ejaculation, likely because of damage to the pelvic autonomic parasympathetic and sympathetic nerves by blunt dissection. The concept of total mesorectal excision (TME) has led to a substantial improvement of autonomic pelvic nerve preservation. This highly precise dissection technique under vision reduces postoperative erectile dysfunction from between 70% and 100% to less than 30%. Another comparison of sexual outcomes of patients with conventional surgery and TME showed that the ability to have intercourse dropped from 75% to 13% in the conventional surgery arm compared with a drop from 67% to 29% in the TME group. A more recent study demonstrated earlier recovery of normal voiding and sexual function for patients undergoing robotic-assisted TME compared with patients who underwent laparoscopic TME. A systematic review examined 10 studies, including 689 patients who underwent rectal cancer surgery. The International Index of Erectile Function scores at 3- and 6-month follow-up were significantly better after robotic-assisted versus laparoscopic surgery. The addition of extended pelvic lymph node dissection is known to adversely influence ejaculatory function. 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 (FSFI) scores that were considered abnormal despite the use of nerve-sparing surgery at the reporting institution.

Gynecologic Surgery

Gynecologic surgical procedures can alter sexual and reproductive function directly by affecting the anatomy of the female genital tract. In one study of 50 women who underwent pelvic surgery for vulvar, cervical, or endometrial cancer, 83% reported sexual problems compared with 20% of the control group. They also reported decreased sexual desire and impaired vaginal lubrication. Onujiogu and colleagues reported a prospective assessment of the prevalence of sexual dysfunction in early-stage (I–IIIa) endometrial cancer patients 1 to 5 years from primary surgical treatment in 72 women. Eighty-nine percent of patients had some form of dysfunction determined by an FSFI score below 26, and pain was the most commonly affected domain. Only 18% of patients received adjuvant therapy, suggesting that sexual dysfunction is prevalent among patients treated with surgery alone. In patients with cervical cancer, radical hysterectomy is associated with negative effects on sexual health. Short-term sexual health consequences include orgasmic problems, vaginal shortening, dyspareunia, genital numbness, and sexual dissatisfaction. Long-term sexual health concerns include lack of sexual interest (25%), genital numbness (71%), and insufficient lubrication (24%). Compared with traditional radical hysterectomy, nerve-sparing radical hysterectomy has shown improvements in short- and long-term bowel and bladder function and improved sexual function. Surgery for ovarian cancer involves bilateral salpingo-oophorectomy, hysterectomy, omentectomy, lymphadenectomy, and tumor debulking. In addition to infertility, ovary removal leads to hormonal alterations that can cause adverse changes in sexual health, leading to more abrupt, prolonged, and intense menopausal symptoms. Among women with breast cancer, several prospective studies have shown no difference in quality of life outcomes or sexual functioning on the basis of surgical treatment. In younger women with breast cancer (age 50 years or younger), sexual problems were significantly greater immediately after surgery, and although these problems decreased over time, they were still greater at 1 year after surgery than before diagnosis.

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