The incidence of infertility is difficult to quantify since infertility is usually only detected when a couple is actively attempting to conceive. It is estimated, however, that infertility is increasing and affects about 15 percent of couples at least once during their reproductive lives when it is defined as the inability to conceive after two years of unprotected intercourse. This is not difficult to fathom when one considers the high number of patients that attend fertility clinics these days.
The causes of infertility in women include the failure to ovulate, endometriosis (when cells that normally grow inside the womb grow outside of it), a lack of or hostile cervical mucus, and tubal damage. In men they may include impotence or retrograde ejaculation among other coital factors, defective sperm, or hypogonadism (when sex glands produce little or no hormones). A cause cannot be found in nearly a third of cases, and the effects of drugs on fertility are not well understood.
It is generally accepted that primary drug-induced infertility occurs due to a toxic effect of the drug either directly on the gonads or indirectly on pituitary gonadotrophins (a hormone that stimulates the activity and development of the gonads). Following are some descriptions of how selected drugs are thought to induce primary infertility (defined as occurring in couples that have never been able to conceive):
- Cytotoxic chemotherapy – these agents interfere with the division of cancer cells and cell repair, and can cause infertility by affecting the gonads directly. Effects depend on the duration of the drug exposure and the stage in the reproductive life of the patient, and they differ in males and females.
At least in males, combination chemotherapy generally appears to result in more lasting effects on reproductive function than single agent treatment. Since it is not possible to monitor the toxic effects of chemotherapy on ovaries, the amount of damage on female reproductive function is inferred from low estrogen levels, increased FSH and LH (hormones similar to those seen at menopause), and amenorrhoea (absence of a menstrual period).
- Alkylating agents – a group of chemotherapy drugs that are highly toxic to the testes. Common agents used include cyclophosphamide (Cytoxan), chlorambucil and fluorouracil (5-FU). Sperm count declines progressively and within several months can lead sometimes to irreversible azoospermia (absence of sperm). Lower doses can lessen the damage and studies have shown that partial recovery of spermatogenesis may occur even many years after treatment with cyclophosphamide and chlorambucil.
Primary ovarian failure has been reported with the use of both melphalan and cyclophosphamide.
- Procarbazine (Matulane) – is an alkylating agent often used in combination with other chemotherapy agents to treat advanced Hodgkin’s disease. It can cause long-term infertility in 10-30 percent of patients.
- Methotrexate (Rheumatrex, Trexall) – able to block the metabolism of cells, it is used to treat breast cancer, psoriasis, and rheumatoid arthritis. It is thought to be less toxic to testes than alkylating agents, even low doses have reportedly caused reversible reductions in sperm count.
- Vincristine – injected intravenously as part of various chemotherapy regimens, it is mainly used to treat lymphomas, lymphoblastic leukemia, and as an immunosuppressant. It is reported to have caused azoospermia.
- Cisplatin – used to treat various types of cancer, lymphomas, and germ cell tumors, it is also reported to have caused azoospermia. Carboplatin and oxaliplatin are newer drugs in the same class as cisplatin whose effects on reproductive function are not well known.
- Sulphasalazine – although mostly used as an anti-inflammatory in the treatment of rheumatoid arthritis, inflammatory bowel disease (IBS) and, more recently, cirrhosis of the liver, its use is being supplanted by mesalazine and other of its derivatives despite their added expense. Sulphasalazine can cause a lower sperm count in men and may result in temporary infertility in both men and women.
- Diethylstilbestrol (DES) – although originally approved in 1941 by the FDA for gonorrheal vaginitis, atrophic vaginitis, postpartum lactation suppression to prevent breast engorgement, and menopausal symptoms, by the 1990s it continued to be approved only for advanced breast cancer in postmenopausal women and advanced prostate cancer. Eli Lilly discontinued making and marketing DES in 1997. The drug has numerous side effects and continues to be a concern because it is known to have caused reproductive tract abnormalities in the children, mostly daughters, of exposed women.
- Anabolic steroids – among other side effects, anabolic steroids can reduce sexual function and cause temporary infertility and testicular atrophy in men, and a temporary reduction of menstrual cycles in women. When taken during pregnancy, they can cause the development of female features in the male fetus and male features in the female fetus.
- Colchicine – used mainly to treat gout and pericarditis (inflammation of the two membranes that surround the heart), it is also being investigated as a potential anti-cancer drug. While there has been no definitive link between colchicine and infertility, the rates of reduced sperm counts or azoospermia in men, and infertility and miscarriage in women being treated with the drug are relatively high.
- NSAIDs – the use of NSAIDs such as aspirin, Advil, Motrin and Aleve can cause ovulation problems by preventing the ovarian follicle to burst and release eggs. Women attempting to conceive should avoid NSAIDs around the time of ovulation.
- Clomiphene citrate (clomid) – used as a fertility drug, it tricks the pituitary gland into secreting FSH and LH hormones that stimulate the maturation of an egg within an ovarian follicle. Ironically, up to a third of clomid users will also develop hostile cervical mucus, which impedes sperm penetration into the uterus and fallopian tubes. Adding a small amount of estrogen from day ten of the menstrual cycle until the LH surge, however, can often improve the quality of the cervical mucus.
- Diltiazem hydrochloride (Cardizem) – a calcium channel-blocking agent used to treat hypertension. Cardizem may reduce male fertility by raising the cholesterol level in sperm.