Effects of fertility drugs on cancers other than breast and gynecologic malignancies.

OBJECTIVE: To examine the relationship of ovulation-stimulating drugs to risk of cancers other than breast and gynecologic malignancies. DESIGN: Retrospective cohort study, with additional follow-up since initial report. SETTING: Reproductive endocrinology practices. PATIENT(S): Among a cohort of 12,193 women evaluated for infertility between 1965 and 1988, a total of 9,892 women (81.1% of the eligible population) were followed through 2010, via passive and active (questionnaire) approaches. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Hazard ratios (HRs) and 95% confidence intervals (CIs) for various fertility treatment parameters for select cancers. RESULT(S): During 30.0 median years of follow-up (285,332 person-years), 91 colorectal cancers, 84 lung cancers, 55 thyroid cancers, and 70 melanomas were diagnosed among study subjects. Clomiphene citrate (CC), used by 38.1% of patients, was not associated with colorectal or lung cancer risks, but was related significantly to melanoma (HR = 1.95; 95% CI: 1.18-3.22), and non-significantly to thyroid cancer risks (HR = 1.57; 95% CI: 0.89-2.75). The highest melanoma risks were seen among those with the lowest drug exposure levels, but thyroid cancer risk was greatest among the heavily exposed patients (HR = 1.96; 95% CI: 0.92-4.17 for those receiving >2,250 mg). Clomiphene citrate-associated risks for thyroid cancer were somewhat higher among nulligravid, compared with gravid, women, but did not differ according to distinct causes of infertility. Gonadotropins, used by only 9.7% of subjects, were not related to risk of any of the assessed cancers. CONCLUSION(S): Our results provide support for continued monitoring of both melanoma and thyroid cancer risk among patients receiving fertility drugs.

Long-term relationship of ovulation-stimulating drugs to breast cancer risk.

BACKGROUND: Although fertility drugs stimulate ovulation and raise estradiol levels, their effect on breast cancer risk remains unresolved. METHODS: An extended follow-up was conducted among a cohort of 12,193 women evaluated for infertility between 1965 and 1988 at five U.S. sites. Follow-up through 2010 was achieved for 9,892 women (81.1% of the eligible population) via passive as well as active (questionnaires) means. Cox regression determined HRs and 95% confidence intervals (CI) for fertility treatments adjusted for breast cancer risk factors and causes of infertility. RESULTS: During 30.0 median years of follow-up (285,332 person-years), 749 breast cancers were observed. Ever use of clomiphene citrate among 38.1% of patients was not associated with risk (HR = 1.05; 95% CI, 0.90-1.22 vs. never use). However, somewhat higher risks were seen for patients who received multiple cycles, with the risk for invasive cancers confirmed by medical records being significantly elevated (HR = 1.69; 95% CI, 1.17-2.46). This risk remained relatively unchanged after adjustment for causes of infertility and multiple breast cancer predictors. Gonadotropins, used by 9.6% of patients, mainly in conjunction with clomiphene, showed inconsistent associations with risk, although a significant relationship of use with invasive cancers was seen among women who remained nulligravid (HR = 1.98; 95% CI, 1.04-3.60). CONCLUSIONS: Although the increased breast cancer risk among nulligravid women associated with gonadotropins most likely reflects an effect of underlying causes of infertility, reasons for the elevated risk associated with multiple clomiphene cycles are less clear. IMPACT: Given our focus on a relatively young population, additional evaluation of long-term fertility drug effects on breast cancer is warranted.

Ovulation-inducing drugs and ovarian cancer risk: results from an extended follow-up of a large United States infertility cohort.

OBJECTIVE: To examine the relationship of ovulation-inducing drugs and ovarian cancer. DESIGN: Retrospective cohort study, with additional follow-up since initial report. SETTING: Five large reproductive endocrinology practices. PATIENT(S): In a retrospective cohort of 9,825 women evaluated for infertility at five clinical sites in the United States between 1965 and 1988 with follow-up through 2010, we examined the relationship of ovulation-inducing drugs and ovarian cancer (n = 85). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Hazard rate ratios (RR) and 95% confidence intervals (CI) for ovarian cancer. RESULT(S): Among women evaluated for infertility, there was no association of ovarian cancer risk with ever use of clomiphene citrate (CC) (adjusted RR 1.34, 95% CI 0.86-2.07) or gonadotropins (RR 1.00, 95% CI 0.48-2.08) and no evidence that any of several more detailed subgroups of usage were related to an increased risk with one exception: women who used CC and remained nulligravid did demonstrate much higher risks than those who successfully conceived compared with nonusers (respectively, RR 3.63, 95% CI 1.36-9.72 vs. RR 0.88, 95% CI 0.47-1.63). CONCLUSION(S): Our overall results were reassuring and consistent with other studies. A reason for an association between CC use and ovarian cancer among persistently nulligravid women remains to be determined. Given the large and increasing number of women treated with ovulation-inducing drugs, the increased risk of ovarian cancer among the subset of women who remained nulligravid should be further monitored.

Fertility drugs and endometrial cancer risk: results from an extended follow-up of a large infertility cohort.

STUDY QUESTION: Do fertility drugs influence the subsequent risk of endometrial cancer in a manner that is independent of other risk predictors, such as parity? SUMMARY ANSWER: In this follow-up of a large cohort of women evaluated for infertility and for whom information was captured on fertility drugs, indications for usage and other risk factors that might influence cancer risk, we found no evidence for a substantial relationship between fertility drug use and endometrial cancer risk. WHAT IS ALREADY KNOWN: Although the hormonal etiology of endometrial cancer has been well established, it remains unclear whether the use of fertility drugs has an influence on risk. Results regarding the effects of fertility drugs on endometrial cancer risk have been inconsistent, although several studies have shown some evidence for possible increases in risk. The relationship is of particular interest given that clomiphene, a commonly prescribed drug, is a selective estrogen receptor modulator, with chemical properties similar to tamoxifen, another drug linked to an increase in endometrial cancer risk. STUDY DESIGN, SIZE, DURATION: In a retrospective cohort of 12 193 women evaluated for infertility between 1965 and 1988 at five US sites, follow-up was pursued through 2010 via both passive as well as active (questionnaire) means. PARTICIPANTS, SETTING, METHODS: Among the 9832 subjects for whom follow-up was allowed and achieved, 259 346 at-risk person-years (i.e. prior to hysterectomy) were accrued, and 118 invasive endometrial cancers identified. Cox regression determined hazard ratios (HRs) and 95% confidence intervals (CIs) for fertility treatments adjusted for endometrial cancer risk factors and causes of infertility. MAIN RESULTS AND THE ROLE OF CHANCE: Although we observed slight increases in endometrial cancer risk associated with clomiphene (HR = 1.39, 95% CI: 0.96-2.01) and the less commonly prescribed gonadotrophins (1.34, 0.76-2.37), there were no convincing relationships of risk with either cycles of use or cumulative exposures for either drug. A statistically significant risk associated with the use of clomiphene among women who began use at younger ages (<30) (1.93, 1.24-3.00) may have reflected indications for drug usage rather than the effect of the drug itself. Women who received clomiphene followed by gonadotrophins were at a non-significantly elevated risk (1.77, 0.98-3.19). LIMITATIONS, REASONS FOR CAUTION: Like most studies of endometrial cancer, we were limited by sample sizes, particularly for evaluating subgroup associations. We were also unable to follow all women and were not able to obtain complete risk factor information (including hysterectomy status) for the entire cohort. WIDER IMPLICATIONS OF THE FINDINGS: Although we found no support for a relationship between fertility drugs and endometrial cancer risk, the association should continue to be monitored given that our study population was still young and had not yet reached the age of peak endometrial cancer incidence. STUDY FUNDING/COMPETING INTEREST(S): This project was supported in part by funds from the intramural research program of the National Cancer Institute, National Institutes of Health. None of the authors has any conflicting interests to declare.

Cancer risk among infertile women with androgen excess or menstrual disorders (including polycystic ovary syndrome).

OBJECTIVE: To define relationships of androgen excesses to cancer risk. DESIGN: Retrospective cohort study. SETTING: Five large infertility practices. PATIENT(S): Among 12,193 women evaluated for infertility during 1965-1988 and traced for cancer incidence through 1999, 2,560 had androgen excess or menstrual disorders; among these, 412 met established criteria for polycystic ovary syndrome. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cancer incidence. Derivation of standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for cancer risk comparisons with the general population and rate ratios (RRs) for comparisons with other infertility patients. RESULT(S): Androgen excess/menstrual disorder patients showed significant SIRs for breast (1.31; 95% CI, 1.05-1.62) and uterine (2.02; 95% CI, 1.13-3.34) cancers and melanoma (1.96; 95% CI, 1.12-3.18). Significant associations for breast and uterine cancers were restricted to primary infertility patients (respective SIRs of 1.53 and 3.48). After adjustment for other cancer predictors, the only excess risk was for uterine cancer among primary infertility patients. Compared with women with secondary infertility and no androgen excess/menstrual disorder, those with primary infertility and a disorder had an RR of 1.88 (95% CI, 0.82-4.32). Cancer risks among the women with polycystic ovary syndrome or androgen excess disorders appeared to be similar to those in the more comprehensive group. CONCLUSION(S): Previous findings linking androgen excess disorders to elevated uterine cancer risks might largely reflect underlying risk profiles.

Melanoma, thyroid, cervical, and colon cancer risk after use of fertility drugs.

OBJECTIVE: This study was undertaken to evaluate melanoma, thyroid, colon, and cervical cancer risks after clomiphene or gonadotropins. STUDY DESIGN: Retrospective cohort of 8422 women (155,527 women-years) evaluated for infertility (1965-1988). Through 1999, cancers were ascertained by questionnaire, cancer and death registries. Poisson regression estimated adjusted rate ratios (RRs). RESULTS: Clomiphene use did not significantly increase risk of melanoma (RR=1.66; 95% CI, 0.9-3.1), thyroid (RR=1.42; 95% CI, 0.5-3.7), cervical (RR=1.61; 95% CI, 0.5-4.7), or colon cancer (RR=0.83; 95% CI, 0.4-1.9). We found no relationship between clomiphene dose or cycles of use and cancer risk at any site. Clomiphene use may impart stronger effects on risks of melanoma (RR=2.00; 95% CI, 0.9-4.6) and thyroid cancer among women who remained nulliparous (RR=4.23; 95% CI, 1.0-17.1). Gonadotropins did not increase cancer risk for these sites. CONCLUSION: Fertility drugs do not appear to have strong effects on these cancers. Nonetheless, follow-up should be pursued to assess long-term risks and to monitor effects among women who remain nulliparous.

Causes of infertility as predictors of subsequent cancer risk.

BACKGROUND: Although studies have found elevated risks of certain cancers linked to infertility, the underlying reasons remain unclear. METHODS: In a retrospective cohort study of 12,193 U.S. women evaluated for infertility between 1965 and 1988, 581 cases of cancer were identified through 1999. We used standardized incidence ratios (SIRs) to compare cancer risk with the general population. Analyses within the cohort estimated rate ratios (RRs) associated with infertility after adjusting for other risk predictors. RESULTS: Infertility patients demonstrated a higher cancer risk than the general population (SIR = 1.23; 95% confidence interval [CI] = 1.1-1.3), with nulligravid (primary infertility) patients at even higher risk (1.43; 1.3-1.6). Particularly elevated risks among primary infertility patients were observed for cancers of the uterus (1.93) and ovaries (2.73). Analyses within the cohort revealed increased RRs of colon, ovarian, and thyroid cancers, and of melanomas associated with endometriosis. Melanomas were linked with anovulatory problems, whereas uterine cancers predominated among patients with tubal disorders. When primary infertility patients with specific causes of infertility were compared with unaffected patients who had secondary infertility, endometriosis was linked with distinctive excesses of cancers of the colon (RR = 2.40; 95% CI = 0.7-8.4), ovaries (2.88; 1.2-7.1), and thyroid (4.65; 0.8-25.6) cancers, as well as melanomas (2.32; 0.8-6.7). Primary infertility due to anovulation particularly predisposed to uterine cancer (2.42; 1.0-5.8), and tubal disorders to ovarian cancer (1.61; 0.7-3.8). Primary infertility associated with male-factor problems was associated with unexpected increases in colon (2.85; 0.9-9.5) and uterine (3.15; 1.0-9.5) cancers. CONCLUSIONS: The effects of infertility may extend beyond gynecologic cancers. Thyroid cancers and melanomas deserve specific attention, particularly with respect to endometriosis.

Uterine cancer after use of clomiphene citrate to induce ovulation.

Clomiphene citrate, a selective estrogen receptor modulator, increases estradiol levels and consequently may increase risk of cancer of the uterine corpus. The authors conducted a retrospective cohort study of 8,431 US women (145,876 woman-years) evaluated for infertility during 1965-1988. Through 1999, 39 uterine cancers were ascertained by questionnaire or cancer and death registries. Poisson regression estimated adjusted rate ratios. Study results suggest that clomiphene may increase uterine cancer risk (rate ratio (RR) = 1.79, 95% confidence interval (CI): 0.9, 3.4) and present evidence of a dose response (p(trend) = 0.07) and latency effect (p(trend) = 0.04). Uterine cancer risk increased with clomiphene dose (RR = 1.93, 95% CI: 0.9, 4.0 for >900 mg), menstrual cycles of use (RR = 2.16, 95% CI: 0.9, 5.2 for >or=6 cycles), and time elapsed since initial use (RR = 2.50, 95% CI: 0.9, 7.2 for women followed for >or=20 years). Risk was more strongly associated with clomiphene among nulligravid (RR = 3.49, 95% CI: 1.3, 9.3) and obese (RR = 6.02, 95% CI: 1.2, 30.0) women, with risk substantially elevated among women who were both obese and nulligravid (RR = 12.52, 95% CI: 1.5, 108.0). Clomiphene may increase uterine cancer risk, with higher doses leading to higher risk. Long-term follow-up of infertility cohorts is necessary to clarify the association between clomiphene use and uterine cancer.

Ovulation induction and cancer risk.

OBJECTIVE: To review and critique the literature regarding ovulation induction and cancer risk. DESIGN: Identification of relevant clinical and epidemiological literature through PubMed and other sources. CONCLUSION(S): Ovulation and associated hormonal changes have been linked with selected cancers, raising concerns regarding ovulation-inducing agents. Clinical studies have suggested potential links, but more definitive analytic investigations have been difficult to interpret given the small numbers, short follow-up, and imprecise information on drugs or indications for usage. Prospective studies have been limited by inabilities to control for other cancer predictors (including parity), while selective recall has been a concern for retrospective studies. Reports of large increases in ovarian cancer risk associated with fertility medications have not been replicated by more recent investigations. Some findings, based on small numbers, suggest slight increases in risk associated with fertility drugs among nulligravid women or after extended follow-up or for certain tumor subtypes, but further replication is needed. Fewer studies have assessed relationships with other hormonally related cancers, but limited findings support the need for further monitoring of long-term effects for breast and endometrial cancers. Findings regarding other cancers are extremely limited but should be pursued for cancers showing evidence of hormonal influences, including colon cancers and melanomas.

Looking at the endometrial biopsy with evidence-based medicine.

The results of the study of endometrial biopsy for the diagnosis of infertility, which appear in this issue, are valid. Likelihood ratios and the receiver operating characteristic curves indicate that an out-of-phase test result is worse than useless; it is misleading.

Ovarian cancer risk associated with varying causes of infertility.

OBJECTIVE: To evaluate the risk of ovarian cancer as related to underlying causes of infertility. DESIGN: Retrospective observational cohort study. SETTING: Five large reproductive endocrinology practices. PATIENT(S): A total of 12,193 women evaluated for infertility between 1965 and 1988. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Ovarian cancer ascertained through 1999. RESULT(S): With 45 identified ovarian cancers, this cohort of infertility patients demonstrated a significantly higher rate of ovarian cancer than the general female population (standardized incidence ratio [SIR] = 1.98; 95% confidence interval [CI], 1.4-2.6). The risk was higher for patients with primary infertility (SIR = 2.73) than for those with secondary infertility (SIR = 1.44), and it was particularly high for patients who never subsequently conceived (SIR = 3.33). Women with endometriosis had the highest risk (SIR = 2.48; 95% CI, 1.3-4.2), with a further elevated risk among those with primary infertility (4.19, 2.0-7.7). Comparisons among the infertile women, which allowed calculation of rate ratios (RRs) after adjustment for multiple factors, also showed links with endometriosis. Compared with women with secondary infertility without endometriosis, patients with primary infertility and endometriosis had a RR of 2.72 (95% CI, 1.1-6.7). CONCLUSION(S): Determination of ovarian cancer risk should take into account the type of infertility (primary vs. secondary) and underlying causes. Further study of endometriosis may provide insights into ovarian carcinogenesis.

Rationing of medical care: Rules of rescue, cost-effectiveness, and the Oregon plan.

Doctors who deal with individual patients fail to avoid interventions with minimal expected benefits. This is one reason that the United States spends more on health care services than any of 28 other industrialized nations. Yet, our money has not bought us health; our infant mortality rate ranks 23rd, and our overall life expectancy rate ranks 20th among the 29 nations. Ours is the only nation without a national health system. Our job-based health insurance system has allowed the number of uninsured persons to reach 44 million, which is 18% of the nonelderly population. This article examines the role of such ethical concepts as beneficence, utilitarianism, and justice in the allocation of health care resources. It also examines the innovative Oregon Health Plan and its use of cost-effectiveness analysis for health care allocation that is based on league tables.

Breast cancer risk associated with ovulation-stimulating drugs.

BACKGROUND: Despite the recognized role of hormones in the aetiology of breast cancer, there has been little evaluation of hormonal preparations used to treat infertility. METHODS: A retrospective cohort study of 12,193 women evaluated for infertility between 1965 and 1988 at five clinical sites identified 292 in situ and invasive breast cancers in follow-up through 1999. Standardized incidence ratios (SIRs) compared breast cancer risks with those of the general population. Analyses within the cohort estimated rate ratios (RRs) associated with medications after adjustment for other breast cancer predictors. RESULTS: Infertile patients had a significantly higher breast cancer risk than the general population [SIR = 1.29, 95% confidence interval (CI) 1.1-1.4]. Analyses within the cohort showed adjusted RRs of 1.02 for clomiphene citrate and 1.07 for gonadotrophins, and no substantial relationships to dosage or cycles of use. Slight and non-significant elevations in risk were seen for both drugs after > or = 20 years of follow-up (RRs = 1.39 for clomiphene and 1.54 for gonadotrophins). However, the risk associated with clomiphene for invasive breast cancers was statistically significant (RR = 1.60, 95% CI 1.0-2.5). CONCLUSIONS: Although there was no overall increase in breast cancer risk associated with use of ovulation-stimulating drugs, long-term effects should continue to be monitored.

Ovarian cancer risk after the use of ovulation-stimulating drugs.

OBJECTIVE: To assess the long-term effects of ovulation-stimulating drugs on the risk of ovarian cancer. METHODS: A retrospective cohort study of 12,193 eligible study subjects (median age 30 years) who were evaluated for infertility during the period of 1965-1988 at 5 clinical sites identified 45 subsequent ovarian cancers in follow-up through 1999. Standardized incidence ratios compared the risk of cancer among the infertile patients to the general population, whereas analyses within the cohort allowed the derivation of rate ratios for drug usage compared with no usage after adjustment for other ovarian cancer predictors. RESULTS: The infertility patients had a significantly elevated ovarian cancer risk compared with the general population (standardized incidence ratio 1.98, 95% confidence intervals [CI] 1.4, 2.6). When patient characteristics were taken into account and risks assessed within the infertile women, the rate ratios associated with ever usage were 0.82 (95% CI 0.4, 1.5) for clomiphene and 1.09 (95% CI 0.4, 2.8) for gonadotropins. There were higher, albeit nonsignificant, risks with follow-up time, with the rate ratios after 15 or more years being 1.48 (95% CI 0.7, 3.2) for exposure to clomiphene (5 exposed cancer patients) and 2.46 (95% CI 0.7, 8.3) for gonadotropins (3 exposed cancer patients). Although drug effects did not vary by causes of infertility, there was a slightly higher risk associated with clomiphene use among women who remained nulligravid, based on 6 exposed patients (rate ratio 1.75; 95% CI 0.5, 5.7). CONCLUSION: The results of this study generally were reassuring in not confirming a strong link between ovulation-stimulating drugs and ovarian cancer. Slight but nonsignificant elevations in risk associated with drug usage among certain subgroups of users, however, support the need for continued monitoring of long-term risks. LEVEL OF EVIDENCE: II-2

Use of frozen semen to avoid human immunodeficiency virus type 1 transmission by donor insemination: a cost-effectiveness analysis.

OBJECTIVE: Reappraisal of current guidelines mandating frozen-thawed semen. DESIGN: Cost-effectiveness analysis comparing the use of frozen semen with the use of fresh semen from the same donors without a second antibody test. SETTING: A Markov model computer simulation. PATIENT(S): A theoretical cohort of 80000 women whose husbands are azoospermic. INTERVENTION(S): Simulation with calculation of costs and payoffs. MAIN OUTCOME MEASURE(S): Total lifetime direct health care costs, costs per live birth, life expectancy, quality adjusted life years (QALY), marginal cost effectiveness (dollar/QALY). RESULT(S): If all 80000 women who undergo donor insemination in the United States each year chose to use fresh semen from donors screened according to the current practice guidelines but without semen cryopreservation, there would be 8881 more births and the mean cost per live birth would be US dollars 15501 less. One recipient would become infected with HIV-1 every 5.1 years, during which time over 180000 noninfected children would be born. The average life expectancy of recipients would be reduced by 2 days, but their quality-adjusted life expectancy would increase by over 1 month. Medicolegal costs to physicians would need to exceed US dollars 780 million per infection to equalize the cost effectiveness of the fresh and frozen policies. CONCLUSION(S): The guidelines should be revised to allow the use of fresh semen by informed recipients.