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Effect of 3-hydroxyphthaloyl-beta-lactoglobulin on vaginal transmission of simian immunodeficiency virus in rhesus monkeys.

Heterosexual transmission of human immunodeficiency virus type 1 (HIV-1) is the major cause of the ongoing AIDS epidemic. Application of chemical barrier methods is expected to contribute to the worldwide control of this epidemic. Bovine beta-lactoglobulin modified by 3-hydroxyphthalic anhydride (3-hydroxyphthalovyl-beta-lactoglobulin [3HP-beta-LG]) was shown to inhibit HIV-1, HIV-2, simian immunodeficiency virus (SIV), herpes simplex virus type 1 and 2, and Chlamydia trachomatis infection in vitro. Here, we show that 3HP-beta-LG not formulated into any vehicle protected three of six rhesus monkeys against vaginal infection by SIV. Incorporation of the compound into an appropriate vehicle is expected to increase the degree of protection. 3HP-beta-LG may be effective as a vaginal inhibitor of HIV-1 infection in humans.

Acquired Immunodeficiency Syndrome↗

Mandelic acid condensation polymer: novel candidate microbicide for prevention of human immunodeficiency virus and herpes simplex virus entry.

Presently marketed vaginal barrier methods are cytotoxic and damaging to the vaginal epithelium and natural vaginal flora when used frequently. Novel noncytotoxic agents are needed to protect men and women from sexually transmitted diseases. One novel candidate is a mandelic acid condensation polymer, designated SAMMA. The spectrum and mechanism of antiviral activity were explored using clinical isolates and laboratory-adapted strains of human immunodeficiency virus (HIV) and herpes simplex virus (HSV). SAMMA is highly effective against all CCR5 and CXCR4 isolates of HIV in primary human macrophages and peripheral blood mononuclear cells. SAMMA also inhibits infection of cervical epithelial cells by HSV. Moreover, it exhibits little or no cytotoxicity and has an excellent selectivity index. SAMMA, although not a sulfonated or sulfated polymer, blocks the binding of HIV and HSV to cells by targeting the envelope glycoproteins gp120 and gB-2, respectively, and also inhibits HSV entry postattachment. SAMMA is an excellent, structurally novel candidate microbicide that warrants further preclinical evaluation.

Antiviral Agents↗

Epidemiology and clinical significance of cervical erosion in women attending a family planning clinic.

Women attending a family planning clinic were studied to determine the relation between cervical erosion and clinical and social characteristics. The appearance of the cervix was recorded without knowledge of the women's symptoms. The prevalence of erosion increased with parity but, when the effects of other factors were controlled, decreased in women aged 35 and over. Erosion was significantly more common in women taking the "pill" and less common in women using barrier methods of contraception than in others. There was considerable variation between doctors in the reporting of erosion. No association was found between erosion and postcoital bleeding, dyspareunia, backache, or dysuria. There was a significant but modest association between erosion and vaginal discharge and a suggestion that erosion may sometimes be associated with nocturia and frequency of micturition. Vaginal flora was similar in women with and without erosion. Cervical erosion should not be regarded as pathological in asymptomatic women, nor should it be assumed necessarily to be the cause of symptoms in women with genitourinary complaints.

Adolescent↗

Fifty ways to leave your rubber: how men in Mombasa rationalise unsafe sex.

OBJECTIVE: To explore the reasons why men who have sex with sex workers in Kenya refuse to use condoms in order to develop potential interventions that might help to overcome these barriers. METHODS: We conducted participant observations over a period of 2 months in the bars, discos, shebeens, and guesthouses of Mombasa, Kenya, where many of the sexual transactions are initiated. RESULTS: Analysis of the participant observations revealed at least 50 reasons for not using a condom, which we grouped into six categories: condoms are not pleasurable, condoms are defective, condoms are harmful, condoms are unnecessary, condoms are too hard to use, and external forces prohibit using condoms. CONCLUSIONS: Some of the reasons men say they do not use condoms would be difficult to affect directly. Others are the result of gaps in knowledge and have not been impacted through better communication strategies. Finally, some of the reasons for not using condoms, such as men's weaknesses, and the loss of pleasure, could possibly be addressed through the introduction of female controlled devices. However, the most important conclusion of this paper is that men who pay for sex do so because it is pleasurable and many men do not find the male condom pleasurable. Therefore, messages targeted at men who have sex with sex workers may not be 100% successful if they only emphasise the benefits of condom use as disease control.

Attitude to Health↗

A survey of female prostitutes at risk of HIV infection and other sexually transmissible diseases.

OBJECTIVE: To determine risk factors for the transmission of human immunodeficiency virus (HIV), including injecting drug use (IDU), sexual behaviour and other sexually transmissible diseases (STDs), in female prostitutes who attended the Sydney Sexual Health (previously STD) Centre. DESIGN: We surveyed by questionnaire 231 (47%) of 491 female prostitutes who visited the Centre over a 19 month period from 1986 to 1988. All were tested for HIV antibody. MAIN OUTCOME: All the women were seronegative for HIV but a number of major risk factors for infection were identified. RESULTS: Seventeen of 26 (65%) current injecting drug users had shared needles in the previous 6 months. Nineteen per cent of those surveyed had bisexual non-paying partners and 21% had partners who injected drugs. Sixty nine per cent always used condoms for vaginal intercourse with paying clients, but they were rarely used with non-paying partners. Condom use was also rare for anal intercourse with clients and/or partners by those (18%) who practised it. Seventeen per cent used condoms alone for contraception and 48% relied on oral contraceptives. We found a reduction in gonorrhoea, herpes and trichomoniasis when compared with a 1985 study conducted at the same Centre. However, there was an increase in reported abnormal cervical cytology. CONCLUSION: In spite of behaviour change by some, there are still many women working as prostitutes in Sydney who remain seriously at risk of HIV infection. We recommend more widespread use of barrier methods of contraception, intensified efforts to prevent the sharing of intravenous needles, closer monitoring of the health of prostitutes, and scientific study of their paying and non-paying sexual partners.

Adolescent↗

Heated intraoperative intraperitoneal mitomycin C and early postoperative intraperitoneal 5-fluorouracil: pharmacokinetic studies.

PURPOSE: The purpose of this study was to report the pharmacokinetics of heated intraoperative intraperitoneal mitomycin C (MMC) and to analyze the impact of heat, extent of peritoneal resections, and effect of intraoperative hyperthermic chemotherapy on the pharmacological properties of the peritoneal plasma barrier. METHODS: Sixty patients with peritoneal carcinomatosis were included in a phase I/II study combining cytoreductive surgery with 2 h of heated intraperitoneal mitomycin C in an intraoperative lavage technique and one cycle of early postoperative 5-fluorouracil (5-FU) given on postoperative days 1-5. Three pharmacokinetic analyses were performed: (1) pharmacokinetics of heated intraoperative intraperitoneal MMC was determined for 18 patients by sampling peritoneal fluid, plasma, and urine during the 2-h procedure; (2) impact of peritoneal resections on MMC pharmacokinetics was assessed by comparing a group of patients who underwent < or = 1 peritonectomy procedure (minimal surgery) to a group of patients who underwent > or = 2 peritonectomy procedures (extensive surgery), and (3) effects of heated intraoperative intraperitoneal chemotherapy on the pharmacokinetics of early postoperative intraperitoneal 5-FU by comparing a group of patients treated with heated intraoperative intraperitoneal MMC to a control group who did not receive heated intraoperative intraperitoneal chemotherapy. RESULTS: The mean dose of heated intraoperative intraperitoneal MMC per patient was 22.5+/-7.1 mg (12.9+/-3.8 mg/m2). Drug absorption from perfusate was 14.3+/-2.7 mg. The mean aeras under the curve (AUC) for perfusate and plasma were, respectively, 340+/-138 and 15+/-4 microg/ml x min. The mean AUC peritoneal fluid/plasma ratio was 23.5+/-5.8. Patients who underwent extensive peritoneal resections exhibited a significantly (p = 0.037; Wilcoxon rank test) increased peak plasma concentration of MMC, a significantly (p = 0.029) increased AUC of plasma concentrations and a significantly (p = 0.034) decreased peritoneal fluid/plasma AUC ratio. Pharmacokinetic studies of early postoperative intraperitoneal 5-FU showed no significant difference in plasma AUC, perfusate AUC and AUC ratio between patients who received and those who did not receive heated intraoperative intraperitoneal MMC. CONCLUSIONS: Heated intraoperative intraperitoneal chemotherapy achieves high peritoneal concentrations of MMC with limited systemic absorption. Systemic drug absorption during heated intraoperative intraperitoneal chemotherapy is increased when extensive peritoneal resections are performed, but such slight increases are unlikely to change the risk of systemic drug toxicities. Heated intraoperative intraperitoneal chemotherapy does not alter the pharmacokinetics of early postoperative intraperitoneal 5-FU.

Antibiotics, Antineoplastic↗

Manometric components of the lower esophageal double hump.

BACKGROUND/AIMS: The lower esophageal sphincter manometry of patients with hiatal hernia often displays a double hump configuration. It seems that this is due to gastric herniation above the high-pressure zone of the crura. This study examines this manometric phenomenon in patients with hiatal hernia and relates it to the lower esophageal antireflux barrier. METHODS: Manometric and 24-hour pH studies of 68 consecutive patients with suspected gastroesophageal reflux disease were analyzed to obtain information regarding the double hump and acid reflux. RESULTS: The findings of a manometric double hump correlated well with the presence of a hiatal hernia of >5 cm. The overall length of the sphincter complex was greater in patients with a double hump, but the length below the respiratory inversion point was constant. Resting pressures at the respiratory inversion point were significantly lower than those measured at either high-pressure zone. The location of the respiratory inversion point was seen most commonly at the superior margin of the distal high-pressure zone. Double hump patients with a negative acid reflux score were found to have higher pressures in the distal high-pressure zone than those patients with acid reflux. CONCLUSIONS: The two high-pressure zones comprising the manometric double hump represent the crural and muscular components of the lower esophageal sphincter. Descriptive information regarding the double hump phenomenon is given, and the importance of the crural component of the lower esophageal sphincter in preventing acid reflux is stressed.

Adult↗

Vitreous: a barrier to nonviral ocular gene therapy.

PURPOSE: Intravitreal injection of therapeutic DNA, complexed to nonviral carriers such as cationic liposomes, may be promising in the treatment of many severe retinal eye diseases. However, after intravitreal injection, such DNA/cationic liposome complexes-called lipoplexes (LPXs)-which are typically hundreds of nanometers in size, must first diffuse through the vitreous before they can reach the retina. The aim of this study was to elucidate whether vitreous is a barrier for the LPXs and to find strategies to overcome this barrier. METHODS: Fluorescent polystyrene nanospheres and LPXs were mixed with vitreous, and their mobility was monitored by fluorescence recovery after photobleaching (FRAP), a microscopy-based technique. The stability of LPXs and naked plasmid DNA in vitreous was studied by gel electrophoresis. RESULTS: We showed that polystyrene nanospheres, in our first experiments used as a model for the LPXs, do not diffuse freely into the vitreous but adhere to fibrillar structures in the vitreous, most likely to collagen fibers. Making the surfaces of the polystyrene nanospheres hydrophilic by attaching hydrophilic polyethylene glycol (PEG) chains at their surfaces circumvented the binding to fibrillar structures in the vitreous. FRAP revealed that "pegylated" polystyrene nanospheres, as long as they are smaller than 500 nm, are indeed mobile in the vitreous. It was further demonstrated that LPXs severely aggregate in vitreous and strongly bind to biopolymers in the vitreous, which immobilizes them completely. However, as observed for the polystyrene nanospheres, coating of the LPXs with PEG averted their aggregation in the vitreous and their binding to fibrillar structures. CONCLUSIONS: Modifying the surfaces of LPXs with hydrophilic PEG chains prevents them from aggregating in vitreous. In this way, LPXs are obtained that can freely move in vitreous, an absolute criterion for reaching the retina after intravitreal injection.

Animals↗

Characteristics of women reporting cervical screening.

The characteristics of women reporting cervical cytology screening has been evaluated using data from control subjects collected in the framework of a case-control study on invasive cervical cancer conducted since 1981 in the greater Milan area. A total of 515 women admitted for nonneoplastic, nongynecologic, nonendocrine-related acute conditions to a network of general and university hospitals were interviewed. The frequency of cervical screening utilization decreased with age: regular screening (greater than or equal to 3 lifetime Pap smears) was reported by 46% of women aged 44 years or less, but only 11% of those aged 65 or more. Married women reported about 50% more frequently occasional (1 or 2) and about three times regular (greater than or equal to 3) cervical screening than unmarried ones. Parous women were more frequently screened, but no trend emerged with number of births. Similarly number of medical consultations in the year before the interview was associated with an increased number of Pap smears. There was no consistent association between number or recency of Pap smears and smoking, sexual habits or education, but women in low social classes tended to be less frequently screened. Ever contraceptive users (oral contraceptives or barrier methods) reported an increased probability to be screened regularly and within two years before the interview.

Adult↗

Perception of HIV and safer sexual behaviors among lesbians.

There is little data on female-to-female transmission of HIV. Some women who have sex with women (WSW) have other high-risk behaviors that could lead to HIV infection. The belief that WSW are at no risk may lead to unsafe sexual practices. In this study, a convenience sample of 78 women was surveyed in order to explore the perception of HIV risk among lesbians, their sexual behaviors, and their sources of information about safer sex. Fifty-three percent reported they were at low risk for contracting HIV. Women reported knowledge of barrier methods (89% to 99%) and no sex during menstruation (92%). However, 35% to 40% reported no knowledge of less common safer sex practices. Women reported their source of knowledge as media (36%), workshops (22%), and friends (12%). Eighty-five percent stated that their health care provider knew they were lesbian, but only 15% reported receiving safer sex education. Nurses and nurse practitioners are aptly poised to provide critical HIV education and health care for this population.

Adult↗

Pre-exposure chemoprophylaxis (PREP) as an HIV prevention strategy.

Chemoprophylaxis may be a prevention strategy for the sexual transmission of human immunodeficiency virus (HIV). Evidence suggests that condom use has waned with the availability of antiretroviral medication, at least in some resource-rich settings. Barrier methods of HIV prevention have inherent problems, and the potential for failure. Microbicide research has focused primarily on male-to-female transmission. Analogous to post-exposure prophylaxis, HIV prevention may be achieved by pre-exposure prophylaxis in some settings. Research in this potential strategy may be rewarding.

Anti-Retroviral Agents↗

Will availability of inhaled human insulin (Exubera) improve management of type 2 diabetes? The design of the Real World trial.

BACKGROUND: Common deterrents to insulin therapy for both physicians and patients are the complexity and burden of daily injections. In January 2006, the first inhaled human insulin (INH, Exubera (insulinhuman [rDNA origin])InhalationPowder) was approved for use in adult patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) in the United States and European Union. Results from the INH clinical trial program have shown comparable efficacy of INH to subcutaneous (s.c.) insulin and superior efficacy versus oral antidiabetic agents; thus providing effective glycemic control in adult patients with T2DM without the requirement for preprandial injections. However, because subjects in those trials were randomized to either INH or an alternative, the studies could not estimate the effect of INH on patient acceptance of insulin therapy. Therefore, traditional study designs cannot provide answers to important and practical questions regarding real world effectiveness, which is influenced by psychological and other access barriers. METHODS: To overcome these limitations, the Real World Trial was designed to estimate the effect of the availability of INH as a treatment option for glycemic control. A total of approximately 700 patients from Canada, France, Germany, Italy, Spain, United Kingdom, and the United States with T2DM poorly controlled by oral agent therapy will be randomized to two different treatment settings. Patients and clinicians in both groups (A & B) may choose from all licensed therapies for diabetes including SC insulin delivered by pens; INH will be an additional treatment option only available in Group A. The Real World Trial (Protocol A2171018) has been registered with ClincalTrials.gov, registration id NCT00134147. RESULTS: The primary outcome for the trial will be the difference in mean glycosylated hemoglobin (HbA1c) at 6 months between groups. The design was based on a preceding feasibility study examining the theoretical effects of inhaled insulin availability on treatment choice in 779 patients. In that study, patients were three times more likely to choose insulin therapy when inhaled insulin was available. CONCLUSION: Innovations in study designs may provide an opportunity to reveal unbiased answers to important treatment questions that are more relevant to prescribers, funding agencies, and healthcare policymakers.

Journal Article↗

Treatment of pregnant patients with antiphospholipid syndrome.

Antiphospholipid Syndrome (APS) has been widely recognized as a risk factor for the recurrence of both thrombosis and pregnancy losses; however the optimal treatment of patients is debatable. The aim of this paper was to establish a consensus among experts on the treatment of APS in pregnancy. A questionnaire that described possible different clinical situations was sent to the International Advisory Board of the 10th International Congress on Antiphospholipid Antibodies. Sixteen experts from different medical branches and different geographic areas sent their replies. The consensus was that treatment for APS pregnant patients should be low molecular weight heparin (LMWH) and low dose aspirin (LDA). The dosage, and frequency of LMWH depends on different situations, including the body weight and past history. Patients with previous thromboses usually receive two injections per day. Warfarin can also be used from 14 to 34 weeks, for patients with previous stroke or severe arterial thromboses. The use of intravenous immunoglobulin (IVIG) seems to be restricted to patients with pregnancy losses despite conventional treatment. The experts usually advised barrier methods of contraception, intrauterine device (if the patient is not taking corticosteroids) or progestins. Oral contraception with oestrogens was usually avoided.

Adult↗

Oral contraceptives and reproductive system cancer.

Extensive research during the last 20 years has shown that oral contraceptives are safe. Several recent epidemiological studies have confirmed that combined oral contraceptives (COCs) provide substantial protection against endometrial and ovarian cancer, and this protection is long-lasting and may persist for 15 or more years after termination of OC use. In many studies COCs have been associated with an increased risk of cervical abnormalities and cervical cancer, but there might be alternative explanations for these epidemiological associations (COC users can start having sexual intercourse at an earlier age, they have more sexual partners, and they rarely use barrier methods of contraception), so OCs act as a promoter for HPV-induced carcinogenesis. Finally, women who are currently using COCs or have used them in the past 10 years are at a slightly increased risk of having breast cancer during the next 10 years, although the additional cancers diagnosed tend to be localized to the breast and they are less advanced clinically than the cancers diagnosed in those who have never used COCs.

Adult↗

Walking forward: the South Dakota Native American project.

BACKGROUND: The "Walking Forward" program is a scientific collaborative program between Rapid City Regional Hospital, the University of Wisconsin, the Mayo Clinic, and partnerships with the American Indian community in western South Dakota-3 reservations and 1 urban population. The purpose is to increase participation of health disparities populations on National Cancer Institute clinical trials as part of the Cancer Disparities Research Partnership program. Clinical practice suggests that Native American cancer patients present with more advanced stages of cancer and hence have lower cure rates and higher treatment-related morbidities. It is hypothesized that a conventional course of cancer treatment lasting 6 to 8 weeks may be a barrier. METHODS: Innovative clinical trials have been developed to shorten the course of treatment. A molecular predisposition to treatment side effects is also explored. These clinical endeavors will be performed in conjunction with a patient navigator research program. RESULTS AND CONCLUSIONS: Research metrics include analysis of process, clinical trials participation, treatment outcome, and assessment of access to cancer care at an early stage of disease.

Breast Neoplasms↗

Serum profiles of free and conjugated neuroactive pregnanolone isomers in nonpregnant women of fertile age.

BACKGROUND: Pregnanolone isomers (PI) with a hydroxy group in the 3alpha-position are neuroinhibitors operating via positive modulation of GABA(A) receptors. The 3beta-PI and sulfates of PI and pregnenolone exert the opposite effect. In addition to the brain's in situ synthesis, some circulating steroids can penetrate the blood-brain barrier. METHODS: To assess the physiological impact of peripheral endogenous neuroactive pregnanolone isomers and their polar conjugates in women, serum allopregnanolone (P3alpha5alpha), isopregnanolone (P3beta5alpha), pregnanolone (P3alpha5beta), epipregnanolone (P3beta5beta), pregnenolone, estradiol (including their polar conjugates), and additional steroids were measured in 16 women in the follicular and luteal phases of the menstrual cycle using gas chromatography/mass spectrometry and RIA for the analysis. Linear models and Spearman's correlations were used for data evaluation. RESULTS AND DISCUSSION: The levels of conjugated PI were from one to almost three orders of magnitude higher in comparison with the free steroids. The results indicate that a substantial proportion of the progesterone is metabolized in the sequence progesterone-->5beta-dihydroprogesterone-->P3alpha5beta-->conjugated P3alpha5beta. The sulfation of PI and particularly of P3alpha5beta moderates the levels of free PI and restrains estradiol biosynthesis via progesterone degradation. PI including the conjugates reflected changing progesterone formation during the menstrual cycle. In the follicular phase, the positive correlation with conjugated pregnenolone, the independence of progesterone, and the negative age relationships of PI indicate their adrenal origin. The dependence on progesterone and the independence of conjugated pregnenolone suggest a gonadal source of PI in the luteal phase. The neuroactivating PI prevailed over neuroinhibiting PI.

Adult↗

Relaxin in the peri-implantation period.

The time of appearance of relaxin in peripheral blood was determined in conceptive and non-conceptive cycles using a sensitive and specific double-antibody enzyme-linked immunoassay for human relaxin. For study of relaxin in early pregnancy, daily plasma samples were collected from women receiving artificial insemination of donor semen. The day of ovulation was determined by daily LH monitoring and ultrasound observation. In three conceptive cycles, relaxin was significantly elevated over baseline 9-10 days following the LH peak. Relaxin concentrations quickly rose over the next 15 days of observation to over 800 pg/ml. Relaxin was observed to increase 1 to 2 days prior to the first detectable increase in plasma hCG as measured by enzyme-linked immunosorbent assay. To compare the relaxin profile in conceptive cycles with normal luteal phase concentrations, relaxin was also measured in daily plasma samples collected from women contracepting with barrier methods, bilateral tubal ligation, or abstinence. A small but consistent rise in relaxin in the late luteal phase was observed in nine of eleven women, which began 6-9 days after the LH peak, averaged approximately 50 pg/ml, and was declining by the next menses. It is concluded that a small but measurable rise in plasma relaxin is associated with the normal luteal phase and that relaxin secretion is accelerated around the time that hCG is first detected in conceptive cycles. This acceleration of relaxin secretion which is associated with the onset of hCG may provide additional evidence for identification of transient early pregnancy.

Chorionic Gonadotropin↗

Enhanced sensitivity to steroid-negative feedback during breast-feeding: low-dose estradiol (transdermal estradiol supplementation) suppresses gonadotropins and ovarian activity assessed by inhibin B.

Breast-feeding reduces fertility, and this seems to be related, in part, to an enhancement of the sensitivity of the GnRH system to the negative feedback effects of estradiol related to suckling. Previously, we showed that short-term treatment with small doses of estradiol delivered transdermally suppress plasma gonadotropin concentrations in breast-feeding women. We have now monitored the effects on ovarian function of longer-term low-dose estradiol treatment using plasma inhibin B and inhibin A concentrations and ultrasonography. Breast-feeding women (n = 45) using barrier methods of contraception were enrolled at 6 weeks postpartum and followed up to 18 weeks PP. Nineteen women agreed to being randomized to wear either an estrogen [transdermal estradiol supplementation (TES); n = 10; Estraderm, 50 microg/24 h] or a placebo (PL; n = 9) patch for 12 weeks, whereas the remaining 26 women acted as untreated controls. TES did not significantly increase plasma estradiol concentrations. Plasma FSH levels decreased from 6.1+/-0.8 U/L to 3.3+/-0.6 U/L after 2 weeks of treatment (P < 0.01) and were lower in the TES group compared with the PL group at all times during the treatment (at least P < 0.05). Plasma LH concentrations in the TES group were lower than in the PL group after 4, 6, 8, and 10 weeks of estrogen treatment (at least P < 0.05). Throughout the study, no ovarian follicles detected by ultrasound were greater than 10 mm in diameter. Nevertheless, after 2 weeks of treatment, plasma inhibin B concentrations were significantly lower in the TES group than in the PL group (15.5+/-5.8 vs. 64.9+/-11.1 ng/L; P < 0.01) and remained significantly (P < 0.01) suppressed throughout the treatment, suggesting a suppression of the functional ovarian activity during TES. Inhibin A levels remained low in all groups (3-45 ng/L) but were suppressed further by TES treatment with no levels greater than 7 ng/L. We conclude that low-dose estradiol treatment given as TES suppresses ovarian activity as measured by inhibins B and A by reducing the secretion of LH and FSH during breast-feeding for several weeks. This supports the concept that suckling-induced suppression of the GnRH system is associated with an enhancement of the negative effects of estradiol on the hypothalamic GnRH system. Furthermore, because the contraceptive efficacy of breast-feeding is complicated by the unpredictable early return of ovarian activity in some women, TES could be the basis for the development of a novel contraceptive for breast-feeding women.

Administration, Cutaneous↗