Bert Scoccia

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

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.

Evidence for a local change in the progesterone/estrogen ratio in human parturition at term

The purpose of this study was to determine if a local change in the concentrations of estrogen and progesterone occurs in the amniotic fluid during human parturition at term. Amniotic fluid was retrieved from 20 women in active labor and from 20 women not in labor. Patients were matched for maternal age and gestational age. Estradiol, estriol, progesterone, and dehydroepiandrosterone sulfate were measured in amniotic fluid by radioimmunoassay. For women in active labor, the median concentrations (range) of these steroid hormones were 2.4 ng/ml (1 to 9.2 ng/ml), 1661.2 ng/ml (556.6 to 3928.1 ng/ml), 12.3 ng/ml (4.7 to 41.4 ng/ml), and 187.5 ng/ml (61.2 to 470 ng/ml), respectively. The median concentrations (range) for women not in labor were 1.6 ng/ml (0.3 to 5.7 ng/ml), 684.2 ng/ml (70.6 to 2103.1 ng/ml), 13.2 ng/ml (7.5 to 63 ng/ml), and 65.6 ng/ml (20 to 334 ng/ml), respectively. Thus spontaneous human parturition at term was associated with significantly increased amniotic fluid concentrations of estradiol, estriol, and dehydroepiandrosterone sulfate (p = 0.02, p = 0.002, p = 0.003, respectively). The progesterone/estrogen ratios (progesterone/estradiol and progesterone/estriol) were significantly lower for women in active labor compared with those not in labor (p = 0.002 and p = 0.0006, respectively). We conclude that a local change in the progesterone/estrogen ratio occurs during human parturition at term.

In vitro fertilization pregnancy rates in levothyroxine-treated women with hypothyroidism compared to women without thyroid dysfunction disorders.

BACKGROUND Untreated hypothyroidism can lead to ovulatory dysfunction resulting in oligo-amenorrhea. Treatment with levothyroxine can reverse such dysfunction and thus should improve fertility. The purpose of this retrospective study was to assess whether in vitro fertilization (IVF) pregnancy rates differ in levothyroxine-treated women with hypothyroidism compared to women without thyroid dysfunction/disorders. METHODS Treated hypothyroid and euthyroid women undergoing IVF at an academic IVF center were studied after Institutional Review Board approval. Women with hypothyroidism were treated with levothyroxine 0.025-0.15 mg/day for at least 3 months to maintain baseline thyrotropin (TSH) levels of 0.35-4.0 μU/mL prior to commencing IVF treatment (HYPO-Rx group). Causes of infertility were similar in both groups with the exception of male factor, which was more common in the HYPO-Rx group. The main outcomes studied were implantation rate, clinical pregnancy rate, clinical miscarriage rate, and live birth rate. RESULTS We reviewed the first IVF retrieval cycle performed on 240 women aged 37 years or less during the period January 2003 to December 2007. Women with treated hypothyroidism (n=21) had significantly less implantation, clinical pregnancy, and live birth rates than euthyroid women (n=219). CONCLUSIONS We conclude that, despite levothyroxine treatment, women with hypothyroidism have a significantly decreased chance of achieving a pregnancy following IVF compared to euthyroid patients. A larger prospective study is necessary to assess confounding variables, confirm these findings, and determine the optimal level of TSH prior to and during controlled ovarian hyperstimulation for IVF.

Fertility drugs and the risk of breast and gynecologic cancers.

The evaluation of cancer risk among patients treated for infertility is complex, given the need to consider indications for use, treatment details, and the effects of other factors (including parity status) that independently affect cancer risk. Many studies have had methodologic limitations. Recent studies that have overcome some of these limitations have not confirmed a link between drug use and invasive ovarian cancers, although there is still a lingering question as to whether borderline tumors might be increased. It is unclear whether this merely reflects increased surveillance. Investigations regarding breast cancer risk have produced inconsistent results. In contrast, an increasing number of studies suggest that fertility drugs may have a special predisposition for the development of uterine cancers, of interest given that these tumors are recognized as particularly hormonally responsive. Additional studies are needed to clarify the effects on cancer risk of fertility drugs, especially those used in conjunction with in vitro fertilization. Because many women who have received such treatments are still relatively young, further monitoring should be pursued in large well-designed studies that enable assessment of effects within a variety of subgroups defined by both patient and disease characteristics.

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.

Risk of obstructive sleep apnea in obese and nonobese women with polycystic ovary syndrome and healthy reproductively normal women

OBJECTIVE To study the risk for obstructive sleep apnea (OSA) in a group of nonobese and obese polycystic ovary syndrome (PCOS) and control women. DESIGN Prospective study. SETTING Academic tertiary care medical center. PATIENT(S) Forty-four women with PCOS and 34 control women. INTERVENTION(S) All of the women completed the Berlin questionnaire for assessment of OSA risk. MAIN OUTCOME MEASURE(S) All of the women underwent fasting determination of androgens, glucose, and insulin. RESULT(S) Women with PCOS were more obese compared with control women. However, there were no differences in BMI once subjects were divided into nonobese (PCOS: n = 17; control: n = 26) and obese (PCOS: n = 27; control: n = 8) groups. Women with PCOS had higher prevalence of high-risk OSA compared with control women (47% vs. 15%). However, none of the nonobese PCOS and control women screened positively for high-risk OSA. Among the obese group, the risk did not differ between groups (77% vs. 63%). CONCLUSION(S) Our findings indicate that even though the risk for OSA in PCOS is high, it is related to the high prevalence of severe obesity. The risk for OSA among nonobese women with PCOS is very low. However, our findings are limited by lack of polysomnographic confirmation of OSA.

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. Cancer Epidemiol Biomarkers Prev; 23(4); 584–93. ©2014 AACR.

Spontaneous bilateral tubal ectopic pregnancy and failed methotrexate therapy: a case report.

Spontaneous bilateral ectopic pregnancy is extremely rare. An unsuspected case of spontaneous bilateral ectopic pregnancy with failure of single-dose methotrexate is presented. We question whether the recommended dose of methotrexate for unilateral ectopic pregnancy is adequate for bilateral tubal pregnancy.

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.