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PROBLEM Injectable hormonal contraceptives (IHC) have been associated with altered mucosal and systemic milieu which might increase HIV risk, but most studies have focused on DMPA and not NET-EN, despite the growing popularity and lower HIV risk associated with the latter in observational studies. METHOD OF STUDY We used high-performance liquid chromatography in combination with tandem triple quadrupole mass spectrometry (HPLC-LC-MS/MS) to measure steroid hormones in plasma samples of CAPRISA004 study participants. Concentrations of 48 cytokines were measured in the cervicovaginal lavage (CVL) and plasma, and their expression was compared between participants with detectable NET-EN (n = 201) versus non-detectable IHC (n = 90). Each log10 cytokine concentration was tested as an outcome in linear-mixed models, with NET-EN detection as the main explanatory variable. Multivariable models were adjusted for potential confounders. RESULTS In bivariate analysis, detectable NET-EN was associated with reduced cervicovaginal M-CSF (P = 0.008), GM-CSF (P = 0.025) and G-CSF (P = 0.039), and elevated levels MIF (P = 0.008), IL-18 (P = 0.011), RANTES (P = 0.005) and IL-1Rα (P

PROBLEM: Injectable contraceptive use may impact immune cell responsiveness and susceptibility to infection. We measured responsiveness of T-cells from women before and after initiating depot medroxyprogesterone acetate (DMPA) or norethisterone enanthate (Net-En). METHOD OF STUDY: Peripheral blood mononuclear cells collected from women aged 18–34 years prior to, at steady state, and nadir concentrations after initiating DMPA (n = 30) or Net-En (n = 36) and from women initiating copper intrauterine device (CU-IUD; n = 32) were stimulated with phorbol myristate acetate and analyzed using flow cytometry. We evaluated percentage change in T-cells expressing programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4). RESULTS: Compared to baseline, there were decreased numbers of CD4+CTLA4+ (P < .001) and CD8+CTLA4+ (P < .01) T-cells following ex vivo stimulation challenge at steady state DMPA concentrations and no differences at nadir concentrations (P = .781 and P = .463, respectively). In Net-En users, no differences in CD4+CTLA4+ T-cells at steady state (P = .087) and nadir concentrations (P = .217) were observed. DMPA users had fewer CD4+PD-1+ (P < .001) and CD8+PD-1+ (P < .001) T-cells at nadir concentrations. Number of CD4+PD-1+ and CD8+PD-1+ T-cells decreased at steady state concentration (P = .002 and P = .001, respectively) and at nadir concentrations after Net-En initiation (P < .001 and P < .001). In CU-IUD users, there were no changes in number of CD4+CTLA4+ (P = .426) and CD8+CTLA4+ (P = .169) and no changes in CD4+PD-1+ (P = .083) and CD8+PD-1+ (P = .936) compared to baseline. CONCLUSION: Activation of T-cells in response to ex vivo stimulation is suppressed at steady state DMPA concentration and resolves at nadir concentration, suggesting DMPA immunosuppressive effects may be transient.

Introduction In many African settings, women concurrently face substantial risk of human immunodeficiency virus type 1 (HIV‐1) infection, sexually transmitted infections (STIs) and unintended pregnancies. Few studies have evaluated STI risk among users of hormonal implants and copper intrauterine devices (IUDs) although these long‐acting reversible contraceptive methods are being promoted widely because of their benefits. Within a prospective study of women at risk for HIV‐1, we compared the risk of acquisition of Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis among women using different contraceptive methods. Methods MTN‐020/ASPIRE was a randomized trial of the dapivirine vaginal ring for HIV‐1 prevention among 2629 women aged 18 to 45 years from Malawi, South Africa, Uganda and Zimbabwe, of whom 2264 used copper IUDs or progestin‐based injectables or implants during follow‐up. Screening for the above STIs occurred semi‐annually. Results Over 3440 person‐years of follow‐up, 408 cases of C. trachomatis (incidence 11.86/100 person‐years), 196 of N. gonorrhoeae (5.70/100 person‐years) and 213 cases of T. vaginalis (6.19/100 person‐years) were detected. C. trachomatis and N. gonorrhoeae incidence were not significantly different across contraceptive methods. T. vaginalis incidence was significantly higher for copper IUD users compared to depot medroxyprogesterone acetate (DMPA), implant and norethisterone enanthate users. Conclusion Among African women at high HIV‐1 risk, STIs were common. Risk of cervical infections did not differ across contraceptive methods. Significantly higher rates of T. vaginalis were observed among progestin‐based methods compared to copper IUD users. Overall, these findings call for more intensive routine screening for STIs, and they support current World Health Organization guidance that women should have a wide range of contraceptive options.

Testosterone administered alone or in combination with progestogens in male contraception induces reversible oligo-azoospermia, but its effects on body composition and metabolism are less known. We analysed anthropometric and metabolic parameters in five groups of 10 males: four receiving testosterone undecanoate (TU: 1000 mg) plus norethisterone enanthate (NETE: 200 mg) at different intervals (every 8 weeks: NETE-8; every 12 weeks: NETE-12; every 6 weeks for 12 weeks and then every 12 weeks: NETE-6/12; every 6 weeks for 12 weeks and then TU plus placebo every 12 weeks: NETE-6/12/0) and one placebo (NETE-0/0) for a total of 48 weeks. Body mass index (BMI) and waist circumference did not change in any groups except for the NETE-8 in which BMI increased significantly (p = 0.02) at the end of the treatment period. Lean body mass (MAMC or AMA) increased significantly in the highest hormonal dose groups (p = 0.04, NETE-6/12; p = 0.004, NETE-8). No differences were observed in glucose levels, insulin sensitivity index and lipid profile as well as in biochemical and cell count parameters in any groups. In conclusion, NETE and TU for 48 weeks were not accompanied by any metabolic changes and any adverse effects. The weight gain of the highest NETE plus TU dosage was mainly because of gain in muscle mass.

20 healthy female volunteers were enrolled in this study and were randomly divided into 2 groups. 1 group received a single injection of norethisterone enanthate (NET-EN) via gluteal muscle; the other group received NET-EN via the deltoid muscle. The study had a crossover design and after the 1st injection period of 8 weeks there was a steroid-free period of 8 weeks. Blood samples were collected weekly. The serum concentrations of norethisterone estradiol and progesterone were measured by radioimmunoassay. It was found that the elimination rate constant T1/2 and area under the curve for the gluteal and deltoid groups were not significantly different. The peak levels of NET in the serum was somewhat high in the deltoid injection group. The ovarian suppression with NET-EN in some women may last only 60 days or less. (authors)

The efficacy incidence of side effects and discontinuation were studied in 50 subjects who received intramuscular norethisterone enanthate (200 mg) in 2 treatment schedules over an 18 month period. Subjects in group A received the injection every 2 months during the study period whereas those in group B received the injection at a 2 month interval for the 1st 6 months and every 3 months thereafter for 18 months. No pregnancy occurred in either group. Longer cycles and a higher incidence of amenorrhea were noted in the group B subjects. The bleeding pattern showed an increase in spotting episodes in group A at the 4th injection following which no apparent difference in the bleeding pattern was noted in the 2 groups. The discontinuation rate was 80% at the end of the study 28% of the subjects having dropped out for amenorrhea 16% for irregular bleeding and spotting and 6% for minor medical complaints. (authors modified)

OBJECTIVE Transdermal testosterone gel treatment is an effective androgen substitution therapy with several advantages over conventional substitution therapies. Whereas side-effects due to overdosing of hypogonadal patients are unlikely, testosterone gel application without protection may cause severe side-effects in other subjects (partners, family members) by contamination. Therefore, the risk of testosterone transfer of a newly developed 2.5% testosterone gel preparation was evaluated. DESIGN In two clinical randomized open single-centre studies on healthy male volunteers the percentage of testosterone remaining on the skin after gel application over time (n = 12) and the possibility of a transfer of testosterone to another person (n = 28) was evaluated. In the second study the endogenous testosterone production in the receiving subjects was suppressed by injecting 400 mg norethisterone enanthate (NETE). RESULTS After 8 h approximately 60% of testosterone applied to the skin could be recovered. When the skin had been previously washed with water, only about 14% of applied testosterone could be recovered. After intense skin contact with a volunteer who had applied testosterone before on his forearm, no increase in testosterone serum levels could be found in NETE-suppressed men. CONCLUSION Although considerable amounts of testosterone remain on the intact skin for several hours after evaporation of the alcohol vehicle, contamination of a second, especially female or prepubertal, subject causing side-effects seems very unlikely.

OBJECTIVE Gestagens are known to suppress gonadotrophins in women and are currently also under investigation for the development of hormonal male contraceptives. The aim of the study was to assess the potential of norethisterone enanthate (NETE) for male contraception. DESIGN AND MEASUREMENTS The suppressive effect of a single injection of 200 mg NETE on serum gonadotrophins, serum testosterone, lipids, spermatogenesis, well-being and sexual function was evaluated in seven healthy men. RESULTS In this single dose study treatment was well tolerated by all volunteers. NETE led to a rapid, profound and significant suppression of serum LH (day 6 - day 10), FSH (day 2 - day 29), testosterone (day 1 - day 29 and day 35) and SHBG (day 6 - day 35). At study end sperm counts were significantly suppressed. Numbers of spontaneous erections (day 17, 23 and 26), number of sexual fantasies (day 20 and 23) as well as libido (day 20 and 26) were significantly decreased compared to baseline. All other parameters including lipids, augmented glucose, testicular volume and well-being showed no significant alterations. CONCLUSION Because of its strong, rapid and sustained suppression of serum FSH and testosterone norethisterone enanthate offers great potential for hormonal male contraception if combined with testosterone esters.

BACKGROUND: Male hormonal contraception has been an elusive goal. Administration of sex steroids to men can shut off sperm production through effects on the pituitary and hypothalamus. However this approach also decreases production of testosterone so add-back therapy is needed. OBJECTIVES: To summarize all randomized controlled trials (RCTs) of male hormonal contraception. SEARCH METHODS: In January and February 2012 we searched the computerized databases CENTRAL MEDLINE POPLINE and LILACS. We also searched for recent trials in ClinicalTrials.gov and ICTRP. Previous searches included EMBASE. We wrote to authors of identified trials to seek additional unpublished or published trials. SELECTION CRITERIA: We included all RCTs that compared a steroid hormone with another contraceptive. We excluded non-steroidal male contraceptives such as gossypol. We included both placebo and active-regimen control groups. DATA COLLECTION AND ANALYSIS: The primary outcome measure was the absence of spermatozoa on semen examination often called azoospermia. Data were insufficient to examine pregnancy rates and side effects. MAIN RESULTS: We found 33 trials that met our inclusion criteria. The proportion of men who reportedly achieved azoospermia or had no detectable sperm varied widely. A few important differences emerged. 1) Levonorgestrel implants (160 mug daily) combined with injectable testosterone enanthate (TE) were more effective than levonorgestrel 125 microg daily combined with testosterone patches. 2) Levonorgestrel 500 mug daily improved the effectiveness of TE 100 mg injected weekly. 3) Levonorgestrel 250 mug daily improved the effectiveness of testosterone undecanoate (TU) 1000 mg injection plus TU 500 mg injected at 6 and 12 weeks. 4) Desogestrel 150 mug was less effective than desogestrel 300 mug (with testosterone pellets). 5) TU 500 mg was less likely to produce azoospermia than TU 1000 mg (with levonorgestrel implants). 6) Norethisterone enanthate 200 mg with TU 1000 mg led to more azoospermia when given every 8 weeks versus 12 weeks. 7) Four implants of 7-alpha-methyl-19-nortestosterone (MENT) were more effective than two MENT implants. We did not conduct any meta-analysis due to intervention differences.Several trials showed promising efficacy in percentages with azoospermia. Three examined desogestrel and testosterone preparations or etonogestrel and testosterone and two examined levonorgestrel and testosterone. AUTHORS CONCLUSIONS: No male hormonal contraceptive is ready for clinical use. Most trials were small exploratory studies. Their power to detect important differences was limited and their results imprecise. In addition assessment of azoospermia can vary by sensitivity of the method used. Future trials need more attention to the methodological requirements for RCTs. More trials with adequate power would also be helpful.

Background Postpartum depression is a common complication of childbirth affecting approximately 13% of women. A hormonal aeitology has long been hypothesised due to the sudden and substantial fluctuation in concentrations of steroid hormones associated with pregnancy and the immediate postpartum period. There is also convincing evidence that oestrogens progestins and related compounds have important central nervous system activity at physiological concentrations. Objectives The primary objective of this review was to assess the effects of oestrogens and progestins including natural progesterone and synthetic progestogens compared with placebo or usual antepartum intrapartum or postpartum care in the prevention and treatment of postpartum depression. Search strategy We searched The Cochrane Pregnancy and Childbirth Group trials register (June 2004) the Cochrane Depression Anxiety and Neurosis Group trials register (July 2004) the Cochrane Central Register of Controlled Trials (July 2004) MEDLINE (1966 to 2004) EMBASE (1980 to 2004) and CINAHL (1982 to 2004). We scanned secondary references and contacted experts in the field. Selection criteria All published and unpublished randomised controlled trials comparing an oestrogen and progestin intervention with a placebo or usual antepartum intrapartum or postpartum care among pregnant women or new mothers recruited within the first year postpartum. Data collection and analysis Two review authors participated in the evaluation of methodological quality data extraction and data analysis. Results are presented using relative risk for categorical data and weighted mean difference for continuous data. Main results Two trials involving 229 women met the selection criteria. Norethisterone enanthate a synthetic progestogen administered within 48 hours of delivery was associated with a significantly higher risk of developing postpartum depression. Oestrogen therapy was associated with a greater improvement in depression scores than placebo among women with severe depression. Authors conclusions Synthetic progestogens should be used with significant caution in the postpartum period. The role of natural progesterone in the prevention and treatment of postpartum depression has yet to be evaluated in a randomised placebo-controlled trial. Oestrogen therapy may be of modest value for the treatment of severe postpartum depression. Its role in the prevention of recurrent postpartum depression has not been rigorously evaluated. Further research is warranted. (authors)

A review of Chinese research initiated since 1963 on oral contraceptives (OCs) long-acting OCs the "visiting pill" injectables and progestogen-releasing vaginal rings is presented. Clinical trials carried out since 1963 on full dose half-dose and quarter-dose norethisterone compound (pill No. 1) and megestrol compound (pill no. 2) in 1965-1969 followed by an 8th-dose of norethisterone in 1976 showed that a decrease in dosage would not reduce the contraceptive efficacy. Research on a monthly oral contraceptive containing quinestrol and various progestogens began in 1967. In 43373 women using the monthly pill in 347178 cycles in 1969-76 contraceptive efficacy was 98.3%/woman-year. With a lower dose pill contraceptive efficacy was 95.67%/woman-year in a study of 10783 women totalling 130020 cycles during 1975-79 but the incidence of side effects was markedly reduced. Progestin No. 1 a new synthetic progestin from megestrol acetate had a significant anti-implantation effect if used before ovulation. Since 1970 9 kinds of visiting pills have been developed for couples who are separated most of the time and see one another only for vacations. These include megestrol-quingestanol chlomadinone-quingestanol and norgestrienone and provide 98% protection with few side effects. A new combined injectable megestrol acetate is an improvement on combined megestrol acetate achieved by replacing the estradiol 17-beta-cyclopentyl propionate by 17-beta-estradiol. In a clinical trial of norethisterone enanthate including 2532 subjects totalling 27816 cycles the contraceptive efficacy rate was 99.9% with few menstrual changes. In a clinical trial of the vaginal ring performed in Shanghai since 1975 contraceptive efficacy among the 2470 users was 97.85%.

Carbohydrate metabolism, as assessed by the intravenous glucose tolerance test (i.v.-GTT), was studied in 19 healthy, non-lactating women who received injectable contraceptives containing either medroxyprogesterone acetate (DMPA) (10 subjects) or norethisterone enanthate (Net-En) (9 subjects). Tests were made prior to treatment and at intervals over a period of 15 months thereafter. Results obtained indicate that carbohydrate metabolism is not impaired by either of the two progestogens, and neither pyruvate nor cortisol concentrations changed significantly over the period of observation. However, the insulin release in response to glucose loading underwent interesting alterations during treatment. These abnormalities returned promptly to normal after withdrawal of treatment.

The responses of a group of all unmarried, sexually active teenagers in a developing country to offers of contraceptive service were assessed in a prospective, 30-month study at a teaching hospital family planning center. Teenagers of this group constituted 7.2% of the clinic population. The default rate was very high (43.0%) and was most noticeable among users of oral contraceptives. The intrauterine device seemed more acceptable, as were injections of norethisterone enanthate. Possible reasons for this pattern of response are given, and the authors suggest giving new consideration to making the intrauterine device more suitable for and acceptable to teenagers of developing countries. The place of norethisterone enanthate in teenage contraception is also discussed.

19 women (average age and parity 32.7 and 8.7) who had had amenorrhea for 6-21 months were using or had used progestogen injections for contraception and were willing to undergo tubal sterilization were selected for study during 1969-1972 at the Birth Control Clinic of Ain-Shams University in Cairo. Patients had received either 150 mg injections of Depomedroxyprogesterone acetate every 3 months for 18 to 30 months (11) or 200 mg injections of norethisterone enanthate every 84 days for 18 to 33 months (8). Biopsies taken from the ovaries during laparotomy were compared with ovarian biopsies from 15 control cases. In the progestogen-treated women 2 microscopic patterns appeared in the ovaries. Follicular suppression ("quiescent gonad") was seen in 8 of the 11 women still under treatment (6 with Depomedroxyprogesterone and 2 with norethisterone enanthate). A multicystic pattern ("aberrant follicular activity") was seen in 11 cases including all 8 with no progestogen treatment for more than 2 months. It may be assumed that the 2 patterns are interrelated and associated with absence of estrogen production. In the quiescent ovaries the remnants of atretic cysts and the patchy fibrosis indicated the cysts had been present before complete follicular suppression. Multiple cysts may signify resumption of FSH activity.

Effects of progestogens including medroxyprogesterone acetate and norethisterone enanthate on involution of the uterus and the subsequent changes in the endometrium and myometrium are considered. 231 lactating women at the birth control clinics of Ain Shams University were studied. The women were divided into 2 groups: the first 112 women received an injectable contraceptive on the 7th puerperal day. Of these 68 were given norethisterone enanthate 200 mg every 84 days and the rest were given medroxyprogesterone acetate 150 mg (Depo-Provera) every 3 months. Group 2 with 119 women were divided into 2 groups and given either progestogen the first injection at the 6th postpartum week. These progestogens do not affect uterine involution and the duration of lochia was similar to that of controls. The endometrium passed through successive stages of quiesence preatrophy and a trophy and fibrosis. The latter occurred much more rapidly in those starting injection on the 7th postpartum day. The myometrium revealed fibrosis and reduced vascularity. It is remarkable that in all subjects stopping norethisterone enanthate the endometrium regained its cyclic pattern within 2-6 months. After discontinuing Depo-Provera the endometrium required a longer period (5-9 months) to regain activity. It may be delayed even more than 9 months.

3 long-acting injectable progestogens given to fertile women for contraceptive purposes during a long period of time are discussed. 2418 women received im 1000 500 300 or 250 mg depomedroxyprogesterone acet ate (MPA) every 6 months or 150 mg every 3 months during 94300 months. 932 women received 150 mg chlormadinone acetate (CA) every 2 months or 250 mg every 2.5 or 3 months during 30000 months and 130 women received 200 mg norethisterone enanthate every 3 months during 2300 months. All of these drugs had very low failure rates that increased with prolonged use. The failure rates of 150 mg MPA and 250 mg CA were extremely low. These injectable progestogens appear to arrest the Graafian follicles just before the final maturation process. 150 mg MPA every 3 months or followed with 300 mg every 6 months and 250 mg CA every 2.5-3 months have high clinical efficacy when evaluated by the life-table method. Acceptability is limited by the tolerance to side effects. Proper instruction of potential users is fundamental to informing then on what they should expect. It is concluded that these progestogens have a valuable role as potent contraceptives in women with high obstetrical risk in those who have completed their family and in patients where effective intrauterine contraception is contraindicated.

Of 331 Egyptian lactation puerperal women 120 (60 control and 60 experimental subjects) were selected for immunoelectrophoretic study immediately after normal delivery to determine the effect of injectable contraceptive progestogens on lactation. 30 of the patients received 150 mg medroxyprogesterone acetate (Depo-Provera) every 3 months beginning on Postpartum Day 7. 30 others received 200 mg norethisterone enanthate (SH 393) every 84 days beginning on Postpartum Day 7. Milk and serum samples were compared with corresponding samples of control patients of nearly the same age and parity on the same slide by the method of Grabar and Williams modified by Scheidegger. These progestogens produced no appreciable changes in the immunoelectrophoretic patterns. 91.7% 95% and 96.6% of the patients had normal IgG IgM and IgA levels respectively. 5 women (8.3%) showed larger thicker IgG arcs than those of controls; 3 women (5%) showed an increase in IgM levels.

Gestagens without additional estrogens have been used as contraceptives either as daily oral tablets or as im injections at 3-month intervals. The major side effects have been bleeding disturbances. Medroxyprogesterone acetate im has inhibited ovulation. The others have disturbed ovarian function but their efficacy depends on uterine factors such as changes in the cervical mucus and the endometrium. A table lists reported daily and im doses months of use and the Pearl index of each of the following compounds: chlormadinoe acetate .5 mg daily megestrol acetate .5 mg daily medroxyprogesterone acetate 150 mg im every 3rd month norethisterone .35 mg daily norethisterone .30 mg daily norethisterone enanthate 200 mg im every 12th week lynestrenol .5 mg daily dl-norgestrel .075 daily d-norgestrel .030 mg daily and quingestanol acetate .3 mg daily.