Long-term risk of hysterectomy and ectopic pregnancy among Vietnamese women using the quinacrine hydrochloride pellet system vs. intrauterine devices or tubal ligation for contraception.

OBJECTIVES: Determine the long-term risk of hysterectomy and ectopic pregnancy in women using the quinacrine hydrochloride pellet system of permanent contraception (QS) relative to the comparable risk in women using Copper T intrauterine device (IUD) or tubal ligation surgery (TL) for long-term or permanent contraception. METHODS: This was a retrospective cohort study, conducted in the Northern Vietnamese provinces of Ha Nam, Nam Dinh, Ninh Binh and Thai Binh. Women who had their first QS procedure, last IUD insertion or TL between 1989 and 1996 were interviewed regarding post-procedure health outcomes approximately 16 years post exposure. RESULTS: A 95% response rate resulted in 21,040 completed interviews. Overall incidence rates were low for both outcomes (91/100,000 women years of follow-up and 22/100,000 women years of follow-up for hysterectomy and ectopic pregnancy, respectively). After accounting for variations in baseline characteristics between women choosing QS vs. the other two contraceptive methods, no significant excess hazard of either hysterectomy or ectopic pregnancy was associated with QS. CONCLUSIONS: No significant excess long-term risk of hysterectomy or ectopic pregnancy was found among a large group of women using QS vs. IUD or TL for contraception after an average 16 years of follow-up.

Long-term risk of reproductive cancer among Vietnamese women using the quinacrine hydrochloride pellet system vs. intrauterine devices or tubal ligation for contraception.

OBJECTIVES: To determine the long-term risk of reproductive tract cancer in women using the quinacrine hydrochloride pellet system of permanent contraception (QS) relative to the comparable risk in women using Copper T intrauterine device (IUD) or tubal ligation surgery (TL) for long-term or permanent contraception. METHODS: This was a retrospective cohort study, conducted in the Northern Vietnamese provinces of Ha Nam, Nam Dinh, Ninh Binh and Thai Binh. Women who had their first QS procedure, last IUD insertion or TL between 1989 and 1996 were interviewed regarding post-procedure health outcomes, particularly reproductive tract cancers. RESULTS: A 95% response rate resulted in 21,040 completed interviews. Reproductive cancer incidence rates were very low (5.77/100,000 women years of follow-up time; 95%CI = 3.72-8.94). No significant excess hazard of reproductive tract cancer was associated with QS. CONCLUSIONS: No significant excess long-term risk of reproductive tract cancer was found after an average 16 years of follow-up among a large group of women using QS vs. IUD/TL for contraception.

Quinacrine sterilization (QS): time for reconsideration.

Dr. Jaime Zipper, the Chilean inventor of the quinacrine method of nonsurgical permanent contraception, was aware that when chest surgeons injected quinacrine into the pleural cavity to treat and prevent reoccurrence of pleural effusion, it resulted in the formation of fibrous adhesions between the lung and costal pleura. Zipper thought that a similar scarring effect could occur in the fallopian tubes if quinacrine was instilled into the uterine cavity. A series of refinements of the methodology culminated in the use of a modified Copper T intrauterine device inserter tube as a delivery system to introduce seven quinacrine pellets into the uterus. This approach with quinacrine sterilization (QS) was introduced into clinical practice in several countries, and a national clinical trial of over 50,000 women was conducted in Vietnam. However, in 1993, the World Health Organization raised concerns that quinacrine might be carcinogenic. This resulted in abandonment of QS in Vietnam and other countries. Subsequent epidemiologic data from extensive human studies do not support an increase in cancer risk. This paper reviews the history, limitations and clinical potential of QS.

A critical examination of the mode of action of quinacrine in the reproductive tract in a 2-year rat cancer bioassay and its implications for human clinical use.

A rat carcinogenicity bioassay (CaBio) of quinacrine was reanalyzed to investigate its mode of tumor induction. Quinacrine's effects in the rat uterus when administered as a slurry in methylcellulose were contrasted with the human clinical experience which uses a solid form of the drug, to determine the relevance of the tumors produced in the rat to safe clinical use of quinacrine for permanent contraception (QS). A review was performed of the study report, dose feasibility studies, and clinical evaluations of women who had undergone the QS procedure. The top three doses of quinacrine in the CaBio exceeded the maximum tolerated dose, and produced chronic damage, including inflammation, resulting in reproductive tract tumors. Chronic inflammation was significantly correlated with the tumors; there was no evidence of treatment-related tumors in animals without chronic inflammation or other reproductive system toxicity. Because such permanent uterine damage and chronic toxicity have not been observed in humans under therapeutic conditions, we conclude that this mode of action for tumor production will not occur at clinically relevant doses in women who choose quinacrine for permanent contraception.

Quinacrine-induced occlusive fibrosis in the human fallopian tube is due to a unique inflammatory response and modification of repair mechanisms.

Quinacrine has been widely used in treatment of parasitic diseases such as malaria and giardiasis, and in the treatment of autoimmune diseases. Quinacrine has also been used as an effective substitute for surgical contraception by causing occlusion of the fallopian tube. This minimally invasive treatment protocol involves intrauterine insertion of the drug in the form of pellets and has been studied in humans in a number of countries, including the United States. Despite its development in the 1970s, the cellular and molecular events induced by quinacrine in the human fallopian tube have not been described. Here we describe a plausible mechanism for quinacrine action in the fallopian tube. This is manifested as an acute pro-inflammatory response in the uterus and fallopian tube, characterized by loss of epithelial cell adhesion. This response relies on properties of gated channels found on the surface of epithelial cells in the reproductive tract. While the uterus returns to normal, the inflammatory response affects the uterotubal junction and transmural segment of the human fallopian tube, and initiates formation of mature collagen in the lumen of the fallopian tube, resulting in its permanent occlusion. The response within the fallopian tube appears similar to the protective mechanisms that have evolved in women to minimize the likelihood of systemic infection from Neisseria gonorrhoeae, and to some extent from Chlamydia trachomatis. This review could assist in development of experimental models used in investigating the mechanisms of fibrotic responses in humans as well as development of techniques for permanent non-surgical female contraception.

An alternative interpretation of, "A lifetime cancer bioassay of quinacrine administered into the uterine horns of female rats".

This companion article offers an alternative interpretation for the quinacrine-induced uterine tumors observed in a 2-year bioassay in rats (CaBio, Cancel et al., 2010), and provides additional data from two new experiments that support a different interpretation and analysis. Our major premise is that the design of the Cancel et al. bioassay was flawed, particularly regarding dose selection that allowed for misinterpretation of carcinogenic activity. We feel the totality of the information provided herein dictates that the doses (70/70, 70/250 and 70/350 mg/kg quinacrine) causing uterine tumors in their study clearly exceeded the maximum tolerated dose (MTD) typically administered in chronic cancer studies. Our new data support this conclusion and serve to explain the development of lesions, especially the uterine tumors, they have reported. We argue that the rat uterus is not a valid surrogate for the human fallopian tube. Further, we maintain that quinacrine is not genotoxic in vivo, as suggested in their paper. In summary, we believe that quinacrine is not carcinogenic in rats at doses that do not exceed the MTD.

Quinacrine sterilization for human immunodeficiency virus-positive women.

OBJECTIVE: To evaluate the safety of nonsurgical quinacrine sterilization for HIV-positive (HIV+) women. DESIGN: An open trial of quinacrine sterilization was carried out in women infected with HIV and women who were HIV negative (HIV-). Comparison of the results with the two groups provided an assessment of the safety and effectiveness of quinacrine sterilization for HIV+ women. SETTING: University Medical School outpatient services. PATIENT(S): A total of 258 women who desired sterilization were offered quinacrine sterilization as a means of limiting family size. Sixty-four were HIV+, and 194 were HIV-. Women who were HIV+ had CD4 counts >200 and were otherwise healthy. INTERVENTION(S): A modified Copper T intrauterine device inserter was used to place 252 mg of quinacrine, divided into seven pellets (36 mg each) into the uterine cavity. Three insertions of this formulation were performed, 1 month apart. Viral load and CD8 and CD4 lymphocytes were measured both before and after quinacrine sterilization and at follow-up visits. Pregnancies and adverse events were recorded carefully. A decrement life table was made to statistically analyze results. RESULT(S) AND MAIN OUTCOME MEASURE(S): No serious adverse event occurred in any patient in this study. Adverse effects related to quinacrine sterilization were abdominal cramping, vulvar itching, nausea, and vaginal bleeding. Vaginal bleeding was the only short-term side effect noted to occur more frequently in HIV-infected women after quinacrine sterilization. Among HIV+ women, 35.9% had complaints of increased bleeding, whereas only 8.2% of those who were HIV- had such complaints, which probably were insertion related. Viral load and the CD4+ and CD8+ lymphocyte measures displayed no statistically significant difference after quinacrine sterilization. CONCLUSION(S): Quinacrine sterilization is a safe method for the sterilization of HIV-infected women and has no short-term effect on the pathology of the disease.

N-Acylethanolamines in human reproductive fluids.

N-Acylethanolamines (NAEs) are an important family of lipid-signaling molecules. Arachidonylethanolamide (anandamide) (AEA), palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) are co-produced from similar phospholipid precursors when neurons are stimulated. AEA is an endogenous agonist (endocannabinoid) for cannabinoid receptors. It binds with higher affinity to type CB1 than to type CB2 cannabinoid receptors. PEA does not bind to CB1, while the hypothesis that it reacts with putative CB2-like receptors has been questioned. OEA does not activate currently known cannabinoid receptors, but it mimics the effects of AEA and cannabinoids in reducing the fertilizing capacity of sea urchin sperm. OEA and PEA also act as entourage compounds by inhibiting the hydrolysis of AEA by fatty acid amide hydrolase. Cannabinoid receptors and/or AEA are present in mammalian reproductive organs including the testis, epididymis, prostate, ovary, uterus, sperm, preimplantation embryo and placenta, as well as prostatic and mammary carcinomas. We now report that analysis by high-performance liquid chromatography/mass spectrometry (HPLC/MS) shows the presence of AEA, PEA, and OEA in human seminal plasma, mid-cycle oviductal fluid, follicular fluid, amniotic fluid, milk, and fluids from malignant ovarian cysts. Previous studies showed that AEA-signaling via cannabinoid receptors regulates capacitation and fertilizing potential of human sperm, early embryonic development and blastocyst implantation into the uterine mucosa of rodents, as well as proliferation of human mammary and prostatic carcinomas. Current results imply that NAEs also may modulate follicular maturation and ovulation, normal and pathological ovarian function, placental and fetal physiology, lactation, infant physiology, and behavior. Collectively, these findings suggest that NAEs in human reproductive fluids may help regulate multiple physiological and pathological processes in the reproductive system, and imply that exogenous cannabinoids delivered by marijuana smoke might impact these processes. This study has potential medical and public policy ramifications because of the incidence of marijuana abuse by adolescents and adults in our society, previously documented reproductive effects of marijuana, and the ongoing debate about medicinal use of marijuana and cannabinoids.

Evidence that anandamide-signaling regulates human sperm functions required for fertilization.

Ejaculated mammalian sperm require several hours exposure to secretions in female reproductive tracts, or incubation in appropriate culture medium in vitro, before acquiring the capacity to fertilize eggs. Arachidonylethanolamide (AEA), also known as anandamide, is a novel lipid-signal molecule that is an endogenous agonist (endocannabinoid) for cannabinoid receptors. We now report that AEA is present in human seminal plasma, mid-cycle oviductal fluid, and follicular fluid analyzed by high-performance liquid chromatography/mass spectrometry. Sperm are sequentially exposed to these reproductive fluids as they move from the vagina to the site of fertilization in the oviduct. Specific binding of the potent cannabinoid agonist [(3)H]CP-55,940 to human sperm was saturable (K(D) 9.71 +/- 1.04 nM), suggesting that they express cannabinoid receptors. R-methanandamide [AM-356], a potent and metabolically stable AEA analog, and (-)delta(9) tetrahydrocannabinol (THC), the major psychoactive constituent of Cannabis, modulated capacitation and fertilizing potential of human sperm in vitro. AM-356 elicited biphasic effects on the incidence of hyperactivated sperm motility (HA) between 1 and 6 hr of incubation: at (2.5 nM) it inhibited HA, while at (0.25 nM) it stimulated HA. Both AM-356 and THC inhibited morphological alterations over acrosomal caps between 2 and 6 hr (IC(50) 5.9 +/- 0.6 pM and 3.5 +/- 1.5 nM, respectively). Sperm fertilizing capacity, measured in the Hemizona Assay, was reduced 50% by (1 nM) AM-356. These findings suggest that AEA-signaling may regulate sperm functions required for fertilization in human reproductive tracts, and imply that smoking of marijuana could impact these processes. This study has potential medical and public policy ramifications because of the incidence of marijuana abuse by adults in our society, previously documented reproductive effects of marijuana, and the ongoing debate about medicinal use of marijuana and cannabinoids.