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INTRODCTION: Human spermatogenesis is a complex process that transforms spermatogonial stem cells through mitosis and meiosis to spermatozoa. Testosterone is the key regulator of the terminal stages of meiosis, adherence of spermatids to Sertoli cells, and spermiation. Follicle-stimulating hormone (FSH) may be required for early spermatogenesis and is important for maintaining normal spermatogenesis in men. Hormonal contraception suppresses FSH, luteinizing hormone, and intratesticular testosterone concentration, resulting in marked suppression of sperm output. RESULTS: Clinical trials using testosterone alone or testosterone plus progestin demonstrate that sustained suppression of sperm concentration to ≤1 million/mL is sufficient to prevent pregnancy in the female partner. New agents that target spermatogenesis could use this as a target for contraceptive efficacy while others that block sperm function or transport may require a lower threshold. When sperm concentrations are suppressed to such low levels, measurement of sperm motility and morphology is technically difficult and unnecessary. With current data from fertile and infertile men, it is not possible to establish a lower limit of sperm motility or percent normal morphology that equates to the prevention of conception. New compounds that decrease sperm motility or alter sperm morphology may need to demonstrate a complete absence of sperm motility or altered morphology in all spermatozoa in the ejaculate. Sperm function tests may be useful depending on the mechanism of action of each new compound. CONCLUSION: Monitoring of sperm surrogate markers to ensure effective contraception relies on laboratories experienced in semen analyses. The development of at-home tests to assess sperm parameters has progressed rapidly. Some tests have been assessed in clinical trials and approved by regulatory agencies for at-home use for fertility assessment. However, caution must be exercised in using these tests as many have not been rigorously validated against semen parameters measured in laboratories by trained technologists using standardized tests defined in the World Health Organization Semen Manual.
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BACKGROUND: Vaginal rings formulated to deliver two drugs simultaneously have potential as user-controlled, long-acting methods for dual prevention of HIV and pregnancy. METHODS: Two phase 1 randomized trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported. RESULTS: There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs with DPV/LNG ring vs. DPV ring use (p = .22), or with DPV/LNG ring continuous vs. cyclic use (p = .67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (Cmax p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (Cmax p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12). CONCLUSIONS: The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal.
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Dispositivos Anticoncepcionais Femininos , Levanogestrel , Pirimidinas , Hemorragia Uterina , Humanos , Feminino , Levanogestrel/farmacocinética , Levanogestrel/administração & dosagem , Levanogestrel/efeitos adversos , Adulto , Pirimidinas/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/administração & dosagem , Dispositivos Anticoncepcionais Femininos/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/administração & dosagem , Adulto Jovem , Pessoa de Meia-Idade , Infecções por HIV/tratamento farmacológicoRESUMO
BACKGROUND: Current options for male contraception are limited to condoms, the withdrawal method, or a vasectomy. Studies indicate that men have expressed growing interest in bearing responsibility for family planning. OBJECTIVES: To review prior studies investigating the role of an androgen-only or androgen with progestin regimen for hormonal male contraception and to provide an update of a promising new hormonal agent, a transdermal gel. DISCUSSION: Thus far, there have been six studies conducted in couples evaluating the contraceptive efficacy of an androgen-only or androgen co-administered with a progestin regimen for hormonal male contraception. The only ongoing study is by the National Institute of Child Health and Human Development, in collaboration with the Population Council. They have developed a novel transdermal gel containing testosterone and segesterone acetate (Nestorone), a progestin. An ongoing phase II study enrolling more than 460 couples has shown great potential with respect to the product's efficacy, safety, reversibility, and acceptability. As this agent advances in development, a rapid at-home test for sperm concentration will provide couples with immediate feedback regarding their potential for pregnancy. CONCLUSION: There is promise for the first-of-its-kind hormonal male contraceptive, a transdermal gel, to achieve market approval for distribution in the United States and elsewhere. Its safety, efficacy, reversibility, and user-control are all appealing qualities that make it readily adoptable for clinical practice.
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OBJECTIVES: To compare the efficacy of emergency contraception (EC) regimens used within 72 hours of unprotected intercourse in individuals weighing ≥80 kg. STUDY DESIGN: We enrolled reproductive-aged healthy women in a multicenter, single-blind, randomized study of levonorgestrel 1.5 mg (LNG1X) and 3.0 mg (LNG2X) and ulipristal acetate 30 mg (UPA) (enrollment goal 1200). Key eligibility requirements included regular cycles, weight >/= 80kg, unprotected intercourse within 72 hours, no recent use of hormonal contraception, a negative urine pregnancy test (UPT), and willingness to abstain from intercourse until next menses. To assess our primary outcome of incidence of pregnancy, participants completed home UPTs; if no menses by 2-weeks post-treatment, or a positive UPT, they returned for an in-person visit with quantitative serum human chorionic gonadotropin and ultrasound. RESULTS: We enrolled and randomized 532; 44 were not dosed or not evaluable for primary end point, leaving an analyzable sample of 488 (173 LNG1X, 158 LNG2X, 157 UPA) with similar demographics between groups (mean age 29.6 years [5.74], body mass index 37.09 kg/m2 [6.95]). Five pregnancies occurred (LNG1X n = 1, LNG2X n = 1, UPA n = 3); none occurred during the highest at-risk window (day of ovulation and the 3 days prior). We closed the study before achieving our enrollment goal because the low pregnancy rate in all groups established futility based on an interim blinded analysis. CONCLUSIONS: Although slow enrollment limited our study power, we found no differences in pregnancy rates between EC regimens among women weighing 80 kg or more. Our results are not able to refute or support differences between the treatment arms. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clincialtrials.gov Clinical trials#: NCT03537768. IMPLICATIONS: Women weighing 80 kg or more experienced no differences in pregnancy rates between oral EC regimens but due to several significant study limitations including sample size and the lack of a study population at high risk of pregnancy, our results are not able to determine if differences in treatment effectiveness exist.
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Anticoncepção Pós-Coito , Levanogestrel , Norpregnadienos , Humanos , Feminino , Levanogestrel/administração & dosagem , Norpregnadienos/administração & dosagem , Adulto , Gravidez , Anticoncepção Pós-Coito/métodos , Método Simples-Cego , Adulto Jovem , Peso Corporal/efeitos dos fármacos , Adolescente , Taxa de GravidezRESUMO
OBJECTIVES: To evaluate ovulation risk among women enrolling in an emergency contraception (EC) study by measuring contraceptive steroids and ovarian hormones. STUDY DESIGN: We used standard chemiluminescent assays to evaluate endogenous hormones (estradiol, progesterone, follicle stimulating hormone, luteinizing hormone) and liquid chromatography-tandem triple quadrupole mass spectrometry to simultaneously analyze concentrations of ethinylestradiol, dienogest, norelgestromin (NGMN), norethindrone (NET), gestodene, levonorgestrel (LNG), etonogestrel (ENG), segesterone acetate, medroxyprogesterone acetate (MPA), and drospirenone in serum samples obtained at the time of enrollment in a recent study comparing oral ulipristal acetate and LNG EC in women with weight ≥80 kg reporting no recent use of hormonal contraception. RESULTS: We enrolled 532 and obtained a valid baseline blood sample from 520 women. Of these, 117 (22.5%) had detectable concentrations of progestin (MPA [n = 58, 11.2%], LNG [50, 9.6%], ENG [11, 2.1%], NET [5, 0.96%], NGMN [3, 0.06%], or drospirenone [1, 0.02%]). LNG was co-detected in all three participants with samples containing NGMN. Multiple progestins were detected in eight other women: ENG/MPA (1), ENG/LNG (2), and MPA/LNG (5). Samples from 55 (10.6%) had concentrations of one or more progestin considered above the minimum level for contraceptive (MPA ≥ 0.1 ng/mL, n = 19; NGMN/LNG ≥ 0.2 ng/mL, n = 31; ENG ≥ 0.09 ng/mL, n = 8; NET ≥ 0.35 ng/mL, n = 4). We detected concentrations of serum progesterone ≥ 3 ng/mL, indicative of luteal phase (postovulation) status, in an additional 194 (37.3%) samples. CONCLUSIONS: More than one-third of enrolled in our clinical trial of oral EC had evidence of prior ovulation at the time of enrollment. Additionally, about 23% had evidence of recent use of hormonal contraception. These results would have decreased the expected risk of pregnancy in the study. IMPLICATIONS: Many participants in a recent clinical trial of oral emergency contraception did not appear to be at risk for pregnancy or would not have benefited from intervention due to cycle timing. Investigators should consider the effects of these findings on expected pregnancy rates when determining sample size in future EC clinical trials, particularly when using noninferiority designs or historical controls.
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Progesterona , Humanos , Feminino , Adulto , Gravidez , Adulto Jovem , Progesterona/sangue , Ovulação/efeitos dos fármacos , Estradiol/sangue , Anticoncepção Pós-Coito/métodos , Hormônio Luteinizante/sangue , Hormônio Foliculoestimulante/sangue , Progestinas/administração & dosagem , Progestinas/sangue , Adolescente , NorpregnadienosRESUMO
OBJECTIVE: To evaluate menstrual cup use and intrauterine device (IUD) expulsion. STUDY DESIGN: We performed a secondary analysis of a 3-year contraceptive efficacy trial comparing two copper 380 mm2 IUDs. Investigators randomized participants approximately 1:4 to the TCu380A or NTCu380-Mini IUD. Approximately 12 months after enrollment began, we advised participants against menstrual cup use due to observed IUD expulsions in cup users. We evaluated IUD expulsion (including spontaneous partial and complete expulsion and accidental self-removal) at 12 and 36 months. We used multivariable logistic regression to evaluate IUD expulsion by age, baseline menstrual volume, body mass index, IUD type, menstrual cup use, parity, and uterine length. RESULTS: This analysis included 1046 participants (203 TCu380A and 843 NTCu380-Mini), with 879 (84.0%) nulliparas. Through 12 and 36 months, expulsion occurred in 74 (7.1%, 95% CI 5.5-8.6%) and 133 (12.7%, 95% CI 10.7-14.7%) participants, respectively. Overall, 250 (23.9%) reported menstrual cup use. More menstrual cup users than non-users experienced expulsion through 12 months (32/203 [15.8%] vs. 42/843 [5.0%]) and 36 months (58/250 [23.2%] vs. 75/796 [9.4%]). Through 36 months, NTCu380-Mini menstrual cup users had higher expulsion odds, while TCu380A cup users did not. Menstrual cup users more frequently experienced accidental self-removal than non-users in participants using the TCu380A (3/53 [5.7%] vs. 0/150 [0.0%]) and the NTCu380-Mini (20/197 [10.2%] vs. 7/646 [1.1%]). In multivariable regression, we found increased odds of expulsion through 36 months in participants using menstrual cups with the NTCu380-Mini (aOR 3.13, 95% CI 1.16-8.46) and <25 years (aOR 1.59, 95% CI 1.07-2.34). CONCLUSIONS: We found higher odds of IUD expulsion with menstrual cup and concurrent NTCu380-Mini IUD use over 36 months of use, but not with concurrent TCu380A IUD use. Menstrual cup users experienced higher likelihood of accidental self-removal regardless of IUD type. IMPLICATIONS: Menstrual cup and NTCu380-Mini use may increase IUD expulsion risk and may increase accidental self-removal risk with TCu380A and NTCu380-Mini use. Clinicians should advise patients of these risks and consider warning patients using an IUD shaped like the NTCu380-Mini (Nova-T frames) of expulsion risk with menstrual cup use.
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Expulsão de Dispositivo Intrauterino , Dispositivos Intrauterinos de Cobre , Produtos de Higiene Menstrual , Humanos , Feminino , Dispositivos Intrauterinos de Cobre/efeitos adversos , Adulto , Adulto Jovem , Modelos LogísticosRESUMO
Male contraceptive development has included use of testosterone (T) with or without a progestin or the use of a single molecule such as progestogenic androgens (PA) for suppression of testicular T production. Expanding upon the vast amount of data accumulated from nortestosterone (NT), NT analogs, and their prodrugs, a new series of PA, the C7 methyl, and ethyl α-substituted T analogs 7α-Methyltestosterone (7α-MT) and 7α-Ethyltestosterone (7α-ET), respectively, were hypothesized and designed to have superior androgenic and progestogenic activities when compared with parent T. Results from androgen receptor and progesterone receptor competitive binding and transcriptional activation assays showed favorable activities for these T analogs. Additionally, 7α-MT and 7α-ET were shown to be active substrates for aromatase in vitro, mitigating a potential negative impact on bone mineral density with long-term use. In conjunction with this observation, the diminished metabolism of these T analogs by 5α-reductase may reduce potential concerns for prostatic growth. In the Hershberger in vivo rat bioassay, 7α-MT and 7α-ET showed superior androgenic and anabolic activities as compared with T. These C7 α-substituted T analogs also showed clear progestogenic activity in the McPhail bioassay which evaluated endometrial glandular arborization in a rabbit model. The discovery of aromatizable molecules with reduced metabolism by 5α-reductase that have androgenic, anabolic, and progestogenic properties indicates that the core and/or prodrugs of 7α-MT and 7α-ET are promising molecules for further development as male contraceptive PAs.
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Anticoncepcionais Masculinos , Nandrolona , Pró-Fármacos , Masculino , Ratos , Coelhos , Animais , Humanos , Androgênios/farmacologia , Androgênios/metabolismo , Testosterona , Progestinas/farmacologia , Nandrolona/farmacologia , Nandrolona/metabolismo , Metiltestosterona , Anticoncepção , Anticoncepcionais Masculinos/farmacologiaRESUMO
Introduction: With high concurrent global rates of HIV incidence and unintended pregnancy, there is a need to provide options beyond condoms to enable users to simultaneously prevent HIV acquisition and pregnancy. Multiple vaginal rings are in development as "MPTs" (multipurpose prevention technologies) as they are shown to provide several co-occurring benefits such as discretion, convenience, reversibility and user control. Methods: In this Phase 1 trial of a 3-month MPT ring in the U.S., 25 participants (low-risk for HIV and pregnancy) were randomized to use the study ring for 90 days continuously or in 28-day cycles with 2-day removal periods in between. All participants completed in-depth interviews at the end of their study participation. Results: Overall, the ring was well tolerated. Participants resoundingly endorsed the concept of an extended-use, dual-purpose vaginal ring, but reported too many functional challenges and side effects to endorse this particular ring. Participants assigned to the continuous regimen reported more positive experiences with ring use than those in the cyclic group. A minority of participants who experienced minimal side effects and did not experience challenges with vaginal retention of the ring found it appealing. However, the majority of participants experienced challenges (ring slippage, expulsions, side effects, vaginal bleeding changes) with product use that outweighed the potential benefits and led them to report that - in the future - they would not be interested in using this specific version of the ring in its current form. A subset expressed interest in using the current MPT ring under certain conditions (e.g., if fewer expulsions, less bleeding, higher risk for HIV/pregnancy). Discussion: User feedback regarding participant experiences and challenges with the study ring was continuously shared with the product developer, underscoring the value of early-stage end-user feedback in product development.
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Injectable male hormonal contraceptives are effective for preventing pregnancy in clinical trials; however, users may prefer to avoid medical appointments and injections. A self-administered transdermal contraceptive gel may be more acceptable for long-term contraception. Transdermal testosterone gels are widely used to treat hypogonadism and transdermal administration may have utility for male contraception; however, no efficacy data from transdermal male hormonal contraceptive gel are available. We designed and are currently conducting an international, multicenter, open-label study of self-administration of a daily combined testosterone and segesterone acetate (Nestorone) gel for male contraception. The transdermal approach to male contraception raises novel considerations regarding adherence with the daily gel, as well as concern about the potential transfer of the gel and the contraceptive hormones to the female partner. Enrolled couples are in committed relationships. Male partners have baseline normal spermatogenesis and are in good health; female partners are regularly menstruating and at risk for unintended pregnancy. The study's primary outcome is the rate of pregnancy in couples during the study's 52-week efficacy phase. Secondary endpoints include the proportion of male participants suppressing sperm production and entering the efficacy phase, side effects, hormone concentrations in male participants and their female partners, sexual function, and regimen acceptability. Enrollment concluded on November 1, 2022, with 462 couples and enrollment is now closed. This report outlines the strategy and design of the first study to examine the contraceptive efficacy of a self-administered male hormonal contraceptive gel. The results will be presented in future reports. IMPLICATIONS: The development of a safe, effective, reversible male contraceptive would improve contraceptive options and may decrease rates of unintended pregnancy. This manuscript outlines the study design and analysis plan for an ongoing large international trial of a novel transdermal hormone gel for male contraception. Successful completion of this and future studies of this formulation may lead to the approval of a male contraceptive.
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Anticoncepcionais Masculinos , Testosterona , Gravidez , Masculino , Humanos , Feminino , Sêmen , Anticoncepção/métodos , Anticoncepcionais , GéisRESUMO
OBJECTIVE: To determine whether a user-controlled sperm concentration test compared with standard semen analysis can effectively monitor spermatogenesis suppression for male contraception. DESIGN: Single center, prospective sub study of the ongoing clinical trial: "Study of daily application of Nestorone and testosterone combination gel for male contraception." SETTING: Research institute at an academic medical center. PARTICIPANT(S): Couples participating in the male contraceptive clinical trial. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): The ability by participants to monitor sperm suppression to a threshold compatible with contraceptive efficacy utilizing a user-controlled test verified by sperm concentration determined by standard laboratory methods. RESULT(S): Thirty-eight men participating in a hormonal male contraceptive clinical trial provided multiple samples during spermatogenesis suppression for this substudy. Participants, employing a user-controlled test, correctly identified the absence of sperm (a negative test) in 100% of their laboratory-confirmed azoospermic samples (n = 122). Participants also identified 100% of samples (n = 73) with sperm >0.2 million/mL as positive. Sperm counts between 0.01 and 0.2 million/mL were identified as negative in 96% of samples. Trial participants noted the overall ease of using the test with respect to sample preparation, test timing, and result interpretation, and that they could accurately use this test at home without difficulty. CONCLUSION(S): Participants undergoing spermatogenesis suppression in a hormonal male contraceptive trial performed user-controlled test to determine whether their semen sperm concentration was ≤ or >0.2 million/mL. Compared with standard semen analyses, participants correctly identified 100% of samples with sperm counts >0.2 million/mL as positive (Sensitivity 100%). A positive result when the couple is using a male contraceptive method triggers the need for semen analysis by a laboratory while the couple uses another method of contraception. Participants correctly diagnosed samples ≤0.2 million sperm/mL as negative in 99% of samples (specificity 99%). A negative result indicates a sperm concentration ≤0.2 million/mL, well below the threshold of ≤1 million/mL offering contraceptive efficacy demonstrated by prior studies. At-home sperm concentration test would minimize the need for users to return to the clinic to monitor suppression of spermatogenesis, decreasing cost and burden of male contraception trials and increasing practicality of the method. CLINICAL TRIAL REGISTRATION NUMBER: NCT: 03452111.
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Anticoncepcionais Masculinos , Testosterona , Masculino , Humanos , Contagem de Espermatozoides , Testosterona/farmacologia , Sêmen , Estudos Prospectivos , Espermatogênese , Análise do Sêmen , Anticoncepção/métodos , EspermatozoidesRESUMO
Dimethandrolone undecanoate (DMAU), an oral investigational male hormonal contraceptive, is a prodrug that is rapidly converted to its active metabolite, dimethandrolone (DMA). Poor and variable oral bioavailability of DMA after DMAU dosing is a critical challenge to develop it as an oral drug. The objective of our study was to elucidate the mechanisms of variable pharmacokinetics of DMA. We first identified DMA metabolites formed in vitro and in vivo in human hepatocyte incubation and serum samples following oral DMAU administration in men, respectively. The metabolite identification study revealed two metabolites, DMA-glucuronide (DMA-G; major) and the androstenedione analog of DMA (minor), in the hepatocyte incubations. After oral DMAU administration, only DMA-G was detected in serum, which was >100-fold compared with DMA levels, supporting glucuronidation as the major elimination mechanism for DMA. Next, 13 clinically relevant UDP-glucuronosyltransferase (UGT) enzymes were tested for their involvement in DMA-G formation, which revealed a major role of UDP-glucuronosyltransferase 2B17 (UGT2B17) isoform with a smaller contribution of UGT1A9 in DMA-G formation. These data were confirmed by dramatically higher DMA glucuronidation rates (>200- and sevenfold) in the high versus the null UGT2B17-expressing human intestinal and liver microsomes, respectively. Since human UGT2B17 is a highly variable enzyme with a 20%-80% gene deletion frequency, the in vitro data suggest a major role of UGT2B17 polymorphism on the first-pass metabolism of DMA. Further, considering DMA is a selective and sensitive UGT2B17 substrate, it could be used as a clinical probe of UGT2B17 activity. SIGNIFICANCE STATEMENT: Dimethandrolone (DMA) is an active metabolite of dimethandrolone undecanoate (DMAU), an investigational male hormonal contraceptive. Previous studies have indicated poor and inconsistent bioavailability of DMAU following oral administration. This study found that UDP-glucuronosyltransferase 2B17-mediated high intestinal first-pass metabolism is the key mechanism of variable DMA bioavailability.
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Anticoncepcionais Masculinos , Humanos , Masculino , Anticoncepcionais Masculinos/metabolismo , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Glucuronídeos/metabolismo , Microssomos Hepáticos/metabolismo , Fígado/metabolismo , Intestinos , Difosfato de Uridina/metabolismoRESUMO
Background: The most widely used copper intrauterine device (IUD) in the world (the TCu380A), and the only product available in many countries, causes side effects and early removals for many users. These problems are exacerbated in nulliparous women, who have smaller uterine cavities compared to parous women. We compared first-year continuation rates and reasons/probabilities for early removal of the TCu380A versus a smaller Belgian copper IUD among nulliparous users. Methods: This 12-month interim report is derived from a pre-planned interim analysis of a sub population and focused on key secondary comparative endpoints. In this participant-blinded trial at 16 centres in the USA, we randomised participants aged 17-40 in a 4:1 ratio to the NT380-Mini or the TCu380A. In the first year, participants had follow-up visits at 6-weeks and 3, 6, and 12-months, and a phone contact at 9 months; we documented continued use, expulsions, and reasons for removal. Among participants with successful IUD placement, we compared probabilities of IUD continuation and specific reasons for discontinuation using log-rank tests. This trial is registered with ClinicalTrials.gov number NCT03124160 and is closed to recruitment. Findings: Between June 1, 2017, and February 25, 2019, we assigned 927 nulliparous women to either the NT380-Mini (n = 744) or the TCu380A (n = 183); the analysis population was 732 (NT380-Mini) and 176 (TCu380A). Participants using the NT380-Mini, compared to the TCu380A, had higher 12-month continuation rates (78·7% [95% CI: 72·9-84·5%] vs. 70·2% [95% CI: 59·7-80·7], p = 0·014), lower rates of removal for bleeding and/or pain (8·1% vs. 16·2%, p = 0·003) and lower IUD expulsion rates (4·8% vs. 8·9%, p = 0·023), respectively. Interpretation: The NT380-Mini offers important benefits for a nulliparous population compared to the TCu380A in the first twelve months, when pivotal experiences typically occur. Higher continuation rates with the NT380-Mini may avert disruptions in contraceptive use and help users avoid unintended pregnancy. Funding: Bill & Melinda Gates Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Mona Lisa, N.V. (Belgium).
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Rates of unplanned pregnancies are high and stagnant globally, burdening women, families and the environment. Local limitations placed upon contraceptive access and abortion services exacerbate global disparities for women. Despite survey data suggesting men and their partners are eager for expanded male contraceptive options, efforts to develop such agents have been stymied by a paucity of monetary investment. Modern male hormonal contraception, like female hormonal methods, relies upon exogenous progestins to suppress the hypothalamic-pituitary-gonadal axis, in turn suppressing testicular testosterone production and sperm maturation. Addition of an androgen augments gonadotropin suppression, more effectively suppressing spermatogenesis in men, and provides androgenic support for male physiology. Previous contraceptive efficacy studies in couples have shown that hormonal male methods are effective and reversible. Recent efforts have been directed at addressing potential user and regulatory concerns by utilizing novel steroids and varied routes of hormone delivery. Provision of effective contraceptive options for men and women is an urgent public health need. Recognizing and addressing the gaps in our contraceptive options and engaging men in family planning will help reduce rates of unplanned pregnancies in the coming decades.
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Anticoncepcionais Masculinos , Contracepção Hormonal , Androgênios/farmacologia , Anticoncepção/métodos , Anticoncepcionais Masculinos/farmacologia , Feminino , Humanos , Masculino , Gravidez , Espermatogênese , Testosterona/farmacologiaRESUMO
Background: Contraceptive-induced menstrual changes (CIMCs) can affect family planning (FP) users' lives in both positive and negative ways, resulting in both opportunities and consequences. Despite this, and despite the important links between FP and menstrual health (MH), neither field adequately addresses CIMCs, including in research, product development, policies, and programs globally. Methods: In November 2020, a convening of both MH and FP experts reviewed the existing evidence on CIMCs and identified significant gaps in key areas. Results: These gaps led to the establishment of a CIMC Task Force in April 2021 and the development of the Global Research and Learning Agenda: Building Evidence on Contraceptive-Induced Menstrual Changes in Research, Product Development, Policies, and Programs Globally (the CIMC RLA) , which includes four research agendas for (1) measurement, (2) contraceptive research and development (R&D) and biomedical research, (3) social-behavioral and user preferences research, and (4) programmatic research. Conclusions: Guided by the CIMC RLA, researchers, product developers, health care providers, program implementers, advocates, policymakers, and funders are urged to conduct research and implement strategies to address the beneficial and negative effects of CIMCs and support the integration of FP and MH. CIMCs need to be addressed to improve the health and well-being of women, girls, and other people who menstruate and use contraceptives globally. Disclaimer : The views expressed in this article are those of the authors. Publication in Gates Open Research does not imply endorsement by the Gates Foundation.
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OBJECTIVE: To assess men's preferences for healthcare provider from whom they would obtain hormonal male contraceptive (HMC) methods. STUDY DESIGN: We asked participants from 3 clinical trials of investigational HMC methods-an oral pill (11ß-Methyl-19-nortestosterone-17ß-dodecylcarbonate, 11ß-MNTDC), intramuscular or subcutaneous injection (Dimethandrolone undecanoate), and transdermal gel (Nestorone and testosterone)-to rank their top 3 preferred HMC providers from a list including: men's health doctor (urologist/andrologist), hormonal doctor (endocrinologist), reproductive health doctor (OB/GYN), family planning clinician (community health worker, midwife, nurse practitioner), regular doctor (family medicine/internal medicine), and community pharmacist. We examined preferences based on their rankings and conducted bivariate analyses. Collapsing the various specialists (men's health doctor, hormonal doctor, reproductive health doctor, and family planning clinician) into a single provider type, we examined participant demographics against provider preference (regular doctor, pharmacist, or specialist). RESULTS: Participants across the 3 trials (n = 124) ranked their regular doctor (44%) and community pharmacist (18%) as their most preferred HMC provider; these preferences did not differ significantly by trial and drug formulation. Specialists in family planning (13%), men's health (12%), reproductive health (10%), and hormones (4%) were least frequently ranked as their preferred provider. Older and higher educated participants more often preferred specialists over regular doctors and pharmacists (p = 0.02 and p = 0.01). CONCLUSIONS: Despite receiving contraceptive steroid hormones and care from endocrinologists and family planning specialists in a clinical trial, participants would prefer to obtain contraception from their regular doctor. IMPLICATIONS: As most men expect to obtain hormonal male contraceptives from their regular doctor when commercially available, primary care physicians should become familiar with HMCs and be prepared to provide counseling and options accordingly.
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Anticoncepcionais Masculinos , Nandrolona , Ensaios Clínicos como Assunto , Anticoncepção/métodos , Anticoncepcionais Masculinos/uso terapêutico , Serviços de Planejamento Familiar , Humanos , Masculino , TestosteronaRESUMO
OBJECTIVES: To describe ovulation inhibition and safety of daily oral ulipristal acetate (UPA) over 84 days. STUDY DESIGN: This multi-center phase 1 and/or 2 trial randomized participants to use oral ulipristal 10 mg or 5 mg daily or a 3 cycle regimen of 5 mg for 24 days followed by four placebo days. We stratified randomization by body mass index (BMI) <32 or 32-40 kg/m2. To estimate ovulation inhibition, the primary outcome, participants underwent transvaginal ultrasound and blood sampling twice weekly; we analyzed compliant participants who completed the 84 day study. Safety endpoints included 3 endometrial biopsies and liver chemistry tests. RESULTS: We enrolled 180 participants and included 137 in the ovulation inhibition analyses. Progesterone values that remained below 3ng/mL throughout treatment suggested consistent ovulation inhibition in 52 of 137 (38%) participants; 25 of 47(53%), 20 of 44(45%), and 7 of 46(15%) among participants randomized to the 10 mg, 5 mg, and cyclic treatments, respectively (p < 0.01). Progesterone values consistently <3 ng/mL were more frequent in participants with a BMI > 32kg/m2 (25/50(50%) vs 27/87(31%), p = 0.01). Average ulipristal concentrations were higher among participants with low progesterone concentrations (p < 0.01). Endometrial biopsies during treatment showed progesterone-receptor-modulator-associated endometrial changes in 52 of 164 participants (32%); 22 of 49(40%), 16 of 48(29%), and 14 of 51(26%) in women randomized to the 10 mg, 5 mg, and the cyclic treatments, respectively (p = 0.07, test-for-trend); these changes resolved after treatment cessation. Liver transaminase changes were rare. CONCLUSIONS: Oral ulipristal acetate over 12 weeks did not reliably suppress ovulation, particularly in the 5 mg cyclic-dose group. Ovulation inhibition and endometrial changes were dose dependent. Reversible endometrial changes occurred during treatment. IMPLICATIONS: Progesterone-receptor modulators have been suggested for daily oral contraception. Since progesterone concentrations suggest that ovulation occurred during treatment, further studies would be necessary to assess whether these were functional ovulations and to evaluate other possible mechanisms of contraception.
Assuntos
Anticoncepcionais Pós-Coito , Norpregnadienos , Feminino , Humanos , Ovulação , Inibição da Ovulação , ProgesteronaRESUMO
The long and challenging drug development process begins with discovery biology for the selection of an appropriate target for a specific indication. Target is a broad term that can be applied to a range of biological entities such as proteins, genes, and ribonucleic acids (RNAs). Although there are numerous databases available for mining biological entities, publicly available searchable, downloadable databases to aid in target selection for a specific disease or indication (e.g., developing contraceptives and infertility treatments) are limited. We report the development of the Contraceptive and Infertility Target DataBase (https://www.citdbase.org), which provides investigators an interface to mine existing transcriptomic and proteomic resources to identify high-quality contraceptive/infertility targets. The development of similar databases is applicable to the identification of targets for other diseases and conditions.
Assuntos
Anticoncepcionais/farmacologia , Bases de Dados como Assunto/estatística & dados numéricos , Desenvolvimento de Medicamentos/instrumentação , Reprodução/efeitos dos fármacos , Humanos , Proteoma , TranscriptomaRESUMO
OBJECTIVES: To assess pharmacodynamic and pharmacokinetic outcomes of a novel copper (Cu) intrauterine system (IUS) releasing ulipristal acetate (UPA) in healthy women. STUDY DESIGN: In this single-blinded, randomized proof-of-concept study, ovulatory women received one of three Cu-IUSs releasing low-dose UPA (5, 20 or 40 µg/d) for 12 weeks. The study included a baseline cycle, three 4-week treatment-cycles and 2 recovery cycles. Primary outcomes included effects of the IUS on bleeding profile, ovarian function, and the occurrence of progesterone receptor modulator associated endometrial changes (PAEC). Pharmacokinetics and safety profile were secondary outcomes. We compared outcomes in treatment-cycle 3 with baseline, using generalized linear mixed models with orthogonal contrasts. RESULTS: We randomized 29 women (5 µg/d = 10, 20 µg/d = 10, 40 µg/d = 9). All had a successful IUS insertion; 27 completed the 12-week treatment period. Compared to baseline, the mean number of bleeding-only days at treatment-cycle 3 declined by 16.7% in the 5 µg/d group (3.6 vs 3.0, p = 0.66), 40.5% in the 20 µg/d group (4.2 vs 2.5, p = 0.14), and 77% in the 40 µg/d group (3.9 vs 0.9, p = 0.002). Most women reported reduction in the amount of bleeding: 4/8, 8/10, and 7/9 for the 5 µg/d, 20 µg/d, and 40 µg/d groups, respectively. During IUS use, ovulation occurred in most cycles [5 µg/d: 23/24 (96%), 20 µg/d: 26/30 (87%), 40 µg/d: 22/27 (81%)]. The frequency of PAEC at IUS removal was 1/10 (10%), 1/10 (10%) and 4/9 (44%) in the 5 µg/d, 20 µg/d, and 4 0 µg/d groups, respectively. No serious adverse events occurred. CONCLUSIONS: Reduction in bleeding, low incidence of PAEC, and no serious adverse events are reassuring findings of the novel Cu-UPA-IUS. The 20 µg/d seems the lowest dose promoting a favorable bleeding profile and limiting PAEC. IMPLICATIONS: The preliminary results of this short-term study of a novel copper intrauterine system (IUS) delivering ulipristal acetate showed reduction of bleeding, low incidence of progesterone receptor modulator associated endometrial changes, and absence of serious adverse events. By preventing copper-induced increase in bleeding, this IUS could provide a noncontraceptive benefit, especially for women with low hemoglobin.
Assuntos
Anticoncepcionais Femininos , Dispositivos Intrauterinos Medicados , Norpregnadienos , Feminino , Humanos , LevanogestrelRESUMO
OBJECTIVE: To determine men's satisfaction with and the potential acceptability of 11ß-methyl-19-nortestosterone dodecylcarbonate (11ß-MNTDC) when used for 28 days as an experimental, once-daily, oral hormonal male contraceptive (HMC). STUDY DESIGN: We surveyed participants from a double-blind, randomized, placebo-controlled, phase 1 clinical trial, examining their experience with and willingness to use daily oral 11ß-MNTDC for male contraception. RESULTS: Of 42 trial participants, 40 (30 11ß-MNTDC, 10 placebo) completed baseline and end-of-treatment surveys. Based on a 28-day experience, few cited any baseline concerns about safety and drug adherence. Following treatment, nearly three-quarters (72.5%) of participants reported satisfaction with the study drug and nearly all (92.5%) would recommend the method to others. More than half of participants would be willing to pay for the study drug (62.5%) and indicated that the method exceeded initial expectations (53.9%). Nearly 90% reported that taking the pill was easy to remember and did not interfere with their daily routines. Approximately one-third of participants reported bothersome side effects (37% 11ß-MNTDC vs. 20% placebo, p = 0.45). Given the option, 42% of participants would prefer a daily HMC pill over injectable regimens or a daily topical gel. CONCLUSION: A majority of participants in this short-term trial of daily oral 11ß-MNTDC reported satisfaction with the regimen, would recommend it to others, and would pay to use the drug as HMC despite some bothersome side effects. IMPLICATIONS: Oral 11ß-MNTDC would be an acceptable and preferable method among men desiring reversible hormonal male contraception (HMC). These data support further trials of novel oral HMCs such as 11ß-MNTDC.