Combined Hormonal Contraceptive Methods

Annovera, a vaginal ring containing segesterone acetate (SA) and ethinyl estradiol (EE), was FDA-approved in 2018. SA, previously called Nestorone, is a 19-norprogesterone derivative which is not orally bioavailable. The ring releases 0.15 mg/day of SA and 0.013 mg/day of EE and is designed for cyclic use (21 days in and 7 days out) to allow for monthly withdrawal bleeding. The same ring is used for 13 cycles (1 year) and does not require refrigeration. This can be more convenient so that patients do not need to obtain periodic refills and may help reduce gaps in contraceptive use. In an analysis of 2 multicenter Phase 3 trials, the Pearl Index (PI) was 2.98 pregnancies per 100 woman-years (95% confidence interval [CI] 2.13 to 4.06) comparable to other recently approved hormonal contraceptive methods. However, the product label states it has not been adequately evaluated in people with a body mass index (BMI) of greater than 29 kg/m ² . Given the prevalence of obesity in the United States was 41.9% in 2017 to 2020, this labeling potentially limits its use in a significant proportion of potential users. In a study investigating pharmacokinetic data of continuous use (no ring removal) of Annovera, predicted daily SA and EE serum levels using a linear regression model were comparable to reported levels in the clinical trials at which pregnancy did not occur. Therefore, continuous use of Annovera may be an effective option for contraception, and future trials are planned.

Twirla is a transdermal contraceptive patch approved by the FDA in 2020 with an average daily exposure of hormones similar to oral contraceptive pills containing 120 mcg levonorgestrel/30 mcg EE. It was designed to have lower steady-state levels of EE compared to the previously approved contraceptive patch containing norelgestromin/EE, which has a mean area under the curve ∼1.6 times higher compared to oral contraceptive pills containing 30 mcg EE/150 mcg levonorgestrel. A multicenter US based Phase 3 trial found a PI of 5.8 (95% CI 4.5–7.2), though the PI varied by BMI from 4.3 (95% CI 2.9–5.8) in people with BMI lesser than 30 kg/m ² to 8.6 (5.8–11.5) in those with BMI ≥30 mg/kg ² . Although Twirla is designed for weekly use for 3 weeks followed by a hormone-free interval of 1 week for regular withdrawal bleeding, a population pharmacokinetic study of 12-week extended patch use found steady-state levonorgestrel and EE levels were achieved by week 3, supporting possible extended patch use. However, the FDA issued a black box warning stating Twirla is contraindicated in people with BMI ≥30 kg/m ² due to reduced effectiveness and possible increased risk for venous thromboembolism (VTE). A postmarketing study to compare VTE risks in new users of Twirla compared to new users of other oral contraceptive methods is in progress.

Another recently approved combined hormonal contraceptive (CHC) is Nextstellis, a pill containing 3 mg drosperinone, a 17-α spirolactone progestin with antimineralocorticoid activity, and 14.2 mg estetrol (E4), a natural estrogen produced by the fetal liver. The E4 used in Nextstellis is synthesized from soy estrone. ^, Nextstellis was FDA-approved in 2021 and contains 24 days of active pills and 4 days of placebo. E4 has selective tissue binding for nuclear estrogen receptor α (endometrium, vagina, and bone) but is antagonistic on membrane estrogen receptor α (breast, liver). This differential activity may be beneficial for bone mineral density while limiting proliferation of benign and malignant breast cell growth and having limited impact on liver function. E4 also has reduced hemostatic effects, which is promising for reduced VTE rates compared with other estrogen-containing contraceptives. E4 has minimal effects on cytochrome P450 (CYP450) enzymes and is minimally metabolized by CYP450 enzymes, which may reduce risk of drug-drug interactions. An analysis of 2 Phase 3 trials in the United States/Canada and Europe/Russia found a PI of 1.52 (95% CI 1.04–2.16), similar to other combined oral contraceptives, with multivariable analysis not finding an association between obesity and efficacy.

Progestin-Only Contraceptive Pills

Two progestin-only pill (POP) options have recently become available in the United States: Slynd, a drospirenone-only pill approved by the FDA in 2019 and Opill, a norgestrel-only pill approved for over-the-counter use without a prescription in 2023. ^, POPs can be used by individuals with medical conditions that are contraindications to estrogen use. However, before the availability of Slynd and Opill, the only POP available in the United States contained 0.35 mg of norethindrone.

Slynd is designed as a 4 mg drospirenone 24/4 pill regimen to allow for scheduled bleeding and to reduce unscheduled bleeding. Despite this, unscheduled bleeding can be common, ranging from 46% in cycle 2 but decreasing in time to 30% in cycle 13, with amenorrhea rates increasing over time. Only 1.9% of study participants discontinued early due to bleeding concerns. Efficacy was high with a PI of 2.9, not affected by BMI. Unlike other progestin-only methods such as prescription-only norethindrone POPs and Opill, the drospirenone-only pill works through ovulation inhibition, allowing for more flexibility for continued contraceptive efficacy in the event of missed pills or 24 hour delays in pill-taking. ^, The drospirenone-only pill is a safe and acceptable estrogen-free option for lactating people.

Norgestrel 75 mcg oral contraceptive pills were previously FDA-approved for prescription use as Ovrette in 1973 but were discontinued by the manufacturer in 2005, not for reasons of safety or effectiveness. ^, Opill was approved as the first over-the-counter oral contraceptive pill in 2023. An analysis of published studies of norgestrel 75 mcg/day estimated an aggregate PI of 2.2, though results should be interpreted with caution since contributing trials were conducted in the 1960s to 1980s when failure rates were likely underestimated compared to modern contraceptive trials using highly sensitive pregnancy tests. In contrast, the Actual Use trial to evaluate the over-the-counter label estimated a PI of 4.4 (95% CI 1.9–8.8).

Norgestrel-only pills primarily work through cervical mucus thickening resulting in mucus unfavorable for fertility, though about two-thirds of people also demonstrate lack of ovulation. ^, The product label reflects need for strict adherence to daily pill-taking with nonhormonal backup contraception recommended for 48 hours if a tablet is taken >3 hours late. However, a randomized crossover study evaluating deliberate non-adherence found that both delayed pill administration by 6 hours and deliberately missing a pill appeared to have little effect on cervical mucus scores and ovulation. Although reassuring about potential efficacy in the event of late pill-taking, additional research is needed before sufficient evidence is available for recommendations to change. As the first over-the-counter contraceptive pill, Opill has potential to increase access to contraception, particularly for those with barriers to health care or inadequate health insurance. Opill also increases access for marginalized or vulnerable populations such as adolescents, minoritized populations, or those living in rural areas or who may have obstacles to visiting health care providers and clinics. However, access to over-the-counter contraception is also dependent on out-of-pocket costs for contraception, including insurance coverage.

Nonhormonal Methods

Phexxi, also called ACIDFORM, Amphora, and EVO100 during its development, was FDA-approved in 2020. Phexxi is a prescription-only vaginal gel containing a 5 gm dose of l -lactic acid, citric acid, and potassium bitartrate. Phexxi is a vaginal pH regulator that works through reducing vaginal pH in the presence of semen to immobilize sperm. As an on-demand contraceptive, it is intended for use up to 1 hour prior to each episode of vaginal intercourse. The Phase 3 study found a cumulative pregnancy percentage of 13.7% (95% CI 10.0–17.5) over 7 cycles, with an estimated PI of 27.5 (95% CI 22.4, 33.5). ^, The most common adverse events were vulvovaginal burning (20%) and vulvovaginal pruritis (11.2%). A post-hoc exploratory analysis of sexual satisfaction found similar to improved sexual satisfaction at the end of the study compared to baseline, possibly due to lubricating effects. Phexxi offers a contraceptive option beyond internal/external condoms, spermicide, and diaphragms for individuals who prefer a patient-controlled, nonhormonal contraceptive.

Phexxi has also been studied as a microbicide to protect against sexually transmitted infections (STIs). In in vitro studies, ACIDFORM was protective against Neisseria gonorrhoeae and herpes simplex virus (HSV) transmission. ^, The mechanism of action is thought to be the pH-modulating, acid-buffering properties, which may help bolster the innate immunity of vaginal fluid. ^, A Phase 2a/3 study found that EVO100 was well-tolerated and reduced rates of Chlamydia trachomatis and gonorrhea infections, but a Phase 3 pivotal trial did not demonstrate efficacy.

Intrauterine Devices

There is currently 1 FDA-approved, nonhormonal intrauterine device (IUD) available in the United States, the copper T 380A IUD, or Paragard. However, there are multiple IUDs available outside of the United States due to increased competition and fewer regulatory barriers, since other regions such as Europe regulate copper IUDs as devices, not drugs, and only need to demonstrate safety instead of efficacy for regulatory approval. In the United States, there have been clinical trials investigating promising new options. The VeraCept copper IUD uses a novel, flexible nitinol frame smaller than the copper T 380A. Nitinol is an alloy of nickel and titanium with pseudo-elasticity and shape memory behaviors commonly used in medical devices such as stents, heart valves, and guidewires. The flexibility of the nitinol frame allows conformation to anatomic variations in uterine size and shape. Additionally, VeraCept contains only 175 mm ² of copper, slightly less than half of the copper T 380A. The lower copper dose may decrease the well-documented side effects of dysmenorrhea and menorrhagia with copper IUDs. A 36-month Phase 2 clinical trial demonstrated a PI of 0.46 (95% CI 0.06–1.67). Adverse events of bleeding, pain, or both prompted 8.1% of participants to discontinue in the first year of use. A Phase 3 open-label study to 3 years with extension to 8 years is underway.

The LevoCept IUD is a hormonal IUD containing levonorgestrel 52 mg and uses the same novel nitinol frame as VeraCept. This is the same dosage as the FDA-approved Mirena and Liletta IUDs, which are approved for contraception for up to 8 years and menorrhagia for 5 years. ^, A 3-year Phase 2 clinical trial demonstrating safety and efficacy of LevoCept for pregnancy prevention is complete, with intention to commence a Phase 3 trial to 3 years with extension up to 5 years in 2025. ^,

Another nonhormonal IUD under investigation in the United States is the Mona Lisa NT Cu380-Mini (NT380-Mini), which uses a smaller Nova-T frame containing 380 mm ² of copper. The NT380-Mini measures 6 mm smaller than Paragard in both the horizontal arms and vertical stem. It is approved for 5 years for contraception in over a dozen European countries and Canada. The smaller design is intended to reduce expulsion and early discontinuation rates related to side effects in a primarily nulliparous population. In a comparison study of nulliparous participants, the NT380-Mini had higher continuation rates (78.7% vs 70.2%), lower rates of removal for bleeding and pain (8.1% vs 16.2%), and lower expulsion rates (4.8% vs 8.9%) than Paragard after 12 months.

There are other innovative IUDs under development with the goal of effective contraception and fewer side effects such as dysmenorrhea and menorrhagia. Preclinical studies of zinc-containing IUDs, a zinc-copper alloy IUD, and a copper-magnesium alloy IUD demonstrate effectiveness at preventing pregnancy in rats, reversibility once removed, and less histologic endometrial inflammation than copper-containing IUDs, suggesting the possibility of an improved side effect profile. A proof-of-concept study assessed a copper IUD delivering a low dose of ulipristal acetate (UPA), a selective progesterone receptor modulator, to decrease the amount of bleeding with copper IUD use. The 12-week study found that 20 mcg/day of UPA was the lowest dose promoting a favorable bleeding profile and limiting endometrial changes. Future investigative trials are needed to demonstrate safety and efficacy of these promising IUDs.

Hormonal Contraceptives

Additional options for combined and progestin-only hormonal contraceptives are in varying stages of development, including vaginal rings, patches, injectables, and innovative delivery systems such as microarray patches.

Vaginal rings combining SA with 17-beta estradiol (E2) are under investigation as a potentially safer combined hormonal contraceptive option due to decreased thromboembolic risk of E2 compared to EE. Two dose-finding studies of a vaginal ring designed for 90-day use have been conducted, with a ring containing SA 200 mcg/day and E2 200 mcg/day being the most favorable dosage for ovulation suppression, avoidance of hypoestrogenism, and favorable bleeding patterns compared to rings containing E2 75 mcg/day and 100 mcg/day. ^, An extension study of 2-day and 4-day ring-free intervals found that the ring-free period provided predictable withdrawal bleeds, which is promising for further study.

A Phase 3 study of a norelgestromin 4.86 mg/EE 0.264 mg transdermal patch is ongoing with study completion projected in early 2025. Compared to the currently available norelgestromin 4.86 mg/EE 0.53 mg transdermal patch, this patch should result in lower systemic levels of EE. Agile Therapeutics, which developed the levonorgestrel/EE patch, Twirla, similarly has transdermal patch concepts in the pipeline such as extended cycle regimens, regimens with a lower-dose patch during week 4 of patch use, and a progestin-only patch, but their pipeline is currently on hold.

In the United States, only 1 contraceptive hormone, depot medroxyprogesterone acetate, is available as a 3-month injectable in a 150 mg intramuscular formulation for contraception and a 104 mg subcutaneous formulation for both contraception and endometriosis-associated pain, although other injectable contraceptives are under development. Levonorgestrel butanoate is an esterified analog of levonorgestrel with potential for a duration of action lasting 4 to 6 months. However, a pilot study of 20 mg and 40 mg micronized LB in obese and nonobese women found that although ovulation was suppressed with a single dose, return to ovulation occurred more quickly than anticipated, including as early as 77 days in 2 individuals. A Phase 1 open-label, dose-ranging pharmacokinetic and pharmacodynamic study of intramuscular and subcutaneous levonorgestrel butanoate at 40 mg, 50 mg, and 60 mg is underway.

There are promising new technologies to deliver contraceptive hormones, including microarray patches, also known as microneedle array patches (MAP). MAPs are microscopic biodegradable polymer microneedles that provide controlled and sustained drug release via a transdermal patch. They are being explored for delivery of vaccines, contraceptives, small molecular drug delivery, and insulin, among other indications. MAPs are designed to be self-administered and essentially painless to apply. A levonorgestrel MAP designed for more than 1 month use, a norelgestromin MAP for 1 to 3 months, and a pericoital Nestorone nanosuspension MAP are under investigation through preclinical in vitro and rat studies.

A study of a placebo effervescent MAP designed to separate the patch backing from the microneedles within a minute of skin insertion demonstrated that the patch was well tolerated and participants were interested in a monthly MAP over monthly hypodermic injections and daily pills. A human-centered design study conducted in Uganda, Gambia, Malawi, and the United Kingdom found that participants viewed the concept of a contraceptive MAP favorably, and preferred a device that was small, easy to use, and provided visual and audio feedback when administered correctly. Opinions on preferred duration of action varied, though the final design for preclinical testing is intended for 6 months of use. Given that various MAPs under development are being designed for use for 1 to 6 months at a time, the varying durations may serve to meet the different contraceptive needs of potential users.

Selective Progesterone Receptor Modulators

Selective progesterone receptor modulators (SPRMs) are estrogen-free compounds that selectively modulate the progesterone receptor by reducing binding of coactivators and enabling binding of corepressors, blocking progestational activity without affecting ovarian estradiol production. Two compounds in this class include mifepristone, which is FDA-approved for medication abortion at a dosage of 200 mg, and UPA, which is FDA-approved for emergency contraception (EC) at a dosage of 30 mg and approved in some countries for treatment of uterine fibroids at 5 mg daily. The estrogen-free aspect of SPRMs could be advantageous for those with contraindications to estrogen; however, there are concerns that chronic administration of an SPRM could result in progesterone receptor modulator-associated endometrial changes (PAEC) similar to endometrial hyperplasia with inactive endometrium and cystically dilated glands.

UPA has been evaluated as a contraceptive via a vaginal ring formulation and a daily 5 mg and 10 mg pill. In a dose-finding parallel group study, a high-dose ring releasing UPA at 2500 mcg/day for 12 weeks demonstrated ovulation suppression for 86.1% of treatment cycles compared to a low-dose ring releasing 1500 mcg/day. Biopsies demonstrated PAEC in 91% of biopsies for women without luteal activity, and in 20% to 22% of biopsies for those with luteal activity in the preceding 30 days. Three cases of heavy or prolonged bleeding occurring in the last month of ring use or after ring discontinuation resulted in a protocol amendment to have participants take a single dose of levonorgestrel 1.5 mg at the end of each 12-week use period to induce a withdrawal bleed. After the protocol amendment, no participants experienced adverse events related to heavy and/or prolonged bleeding, demonstrating potential feasibility of this strategy.

A Phase 1/2 randomized parallel group study of continuous UPA 10 mg orally for 84 days, continuous UPA 5 mg orally for 84 days, and a cyclic regimen of 5 mg UPA daily for 24 days followed by 4 placebo pills for 3 cycles found consistent ovulation inhibition for 53%, 45%, and 15% of participants, respectively. Biopsies were performed between days 70 to 80 while on treatment and at the proliferative phase end-of-study visit, and found that the incidence of PAEC was 40%, 29%, and 26% during treatment in participants using the 10 mg, 5 mg, and cyclic treatment regimens, respectively, and resolved in the posttreatment biopsy. Since oral UPA did not consistently suppress ovulation, further research is needed to determine potential mechanisms of action and efficacy of UPA for contraception. However, there are concerns about potential liver toxicity of UPA due to postmarketing cases in Europe of severe liver injury associated with use of UPA 5 mg daily for 3 months at a time during treatment of uterine fibroids, which may be a rare idiosyncratic drug-induced liver injury response. ^, Since the use of UPA for treatment of fibroids was restricted in Europe in 2021 to premenopausal women who are not candidates for surgical treatment of fibroids, this safety concern about chronic UPA use may limit further contraceptive development.

Nonhormonal Methods

Currently available reversible nonhormonal contraceptives include barrier methods such as condoms, diaphragms, and cervical caps, copper IUDs, spermicides, Phexxi, and fertility awareness-based methods. Other than the copper IUD, these methods are among the less effective methods of contraception. ^, Thus, there is a need for highly effective nonhormonal contraceptive methods including highly effective on-demand methods.

Ovaprene is a nonhormonal monthly vaginal contraceptive comprised of a 55 mm silicone ring releasing ferrous gluconate to cause spermiostasis and a central permeable barrier to inhibit sperm movement and allow passage of fluids. Ovaprene is inserted into the vagina at the end of one menstrual period, left in place to cover the cervix, and then removed at the start of the subsequent menses. Two studies involving postcoital testing found fewer than 5 progressively motile sperm per high power field, meeting criterion for potential contraceptive efficacy. The most common adverse events were bacterial vaginosis and vaginal odor. A pivotal Phase 3 study is underway with study completion estimated in late 2025.

Pericoital Contraception

Pericoital contraception is contraception used at or around the time of intercourse. Currently available on-demand contraception includes levonorgestrel EC and UPA EC, though efficacy can vary by both BMI and cycle day of intercourse. Various studies are investigating ways to improve efficacy of oral EC. Some studies have demonstrated that taking a cyclo-oxygenase-2 inhibitor such as meloxicam in conjunction with levonorgestrel or UPA improves the efficacy of delaying or disrupting follicular rupture. Two Phase 2 studies to evaluate delay in ovulation after taking levonorgestrel 1.5 mg with meloxicam 15 mg in normal weight and obese women are ongoing with study completion expected in late 2024 and early 2025, respectively. ^,

Immunocontraception using antisperm antibodies is under investigation as on-demand methods and via intravaginal ring delivery. Antisperm antibodies are human monoclonal antibodies directed against CD52 g, a glycoprotein present on sperm. ^, A Phase 1 proof-of-concept postcoital and safety study of ZB-06, a vaginal film containing a human contraceptive antibody called HC4-N, found that only 0.04 (±0.06) progressively motile sperm per high power field were detected after intercourse with one-time use of the vaginal film. A postcoital follow-up visit found the effects were reversible with normal sperm penetration into ovulatory mucus 1 month later. There were no treatment-emergent adverse events deemed related to the study product, which is promising for further evaluation of this nonhormonal on-demand contraceptive product.

Permanent Contraception

Among contraceptive users aged 15 to 49 in 2018, female permanent contraception was the most commonly used method (28%). This is accomplished by laparoscopic surgical techniques or postpartum after a vaginal or cesarean delivery primarily by tubal ligation, occlusion, or salpingectomy. In 2002, a hysteroscopic sterilization device known as Essure (Model ESS305) was FDA-approved. Essure was a nickel-titanium alloy coil placed via hysteroscopy into the fallopian tubes and designed to induce fibrosis and tubal occlusion over 3 months to prevent fertilization. This allowed permanent contraception to be available in an office setting without risks of abdominal surgery or general anesthesia. However, in 2016, the FDA convened a meeting due to safety concerns such as tubal perforation and intractable pain with Essure, after which Bayer, the company that marketed Essure, withdrew it from the market at the end of 2018. ^, A clinical trial for the Essure Model ESS505 is ongoing to evaluate a design modification with a hydrogel component attached to the distal end of the insert to produce immediate contraception by plugging the fallopian tube, removing the 3-month waiting period for the original model to be effective. With the removal of Essure from the market, investigators are designing alternative options for individuals seeking permanent contraception who are unable or unwilling to undergo abdominal surgery.

Naturally occurring infectious processes in the fallopian tubes can cause an inflammatory response and fibrosis, resulting in infertility. This is the same effect that Essure and other investigational permanent contraceptives aim to induce in individuals seeking to avoid pregnancy. One such investigational method is FemBloc, a liquid biopolymer implant delivered in-office by balloon catheters. When the biopolymer contacts tissue in the fallopian tubes, it solidifies and leads to scar tissue formation. The biopolymer degrades and expels within 3 months, leaving fibrosis that blocks the tubes, preventing pregnancy. A pivotal trial started in 2023 and will follow participants for 5 years, with study completion estimated in June 2031.

Another potential permanent contraception option is drug-eluting polyester microparticles. In vivo studies in a rhesus macaque animal model demonstrate sclerosing agents, such as doxycycline and phenyl benzoate, elicit acute inflammation in fallopian epithelial tissue. These agents can be formulated into a biomaterial drug delivery system by electrospinning both chemicals into polyester nanofibers with high efficiency. A validation study in a guinea pig uterine horn model found sustained inflammation in groups containing the nanofibers. This represents a new strategy to deliver drugs with the goal of tubal occlusion.

Male Contraceptives

Currently available male-controlled contraceptives include external (male) condoms, withdrawal, and vasectomy. Since spermatogenesis typically takes 68 days for maturation and produces several million sperm per day, reversible suppression of spermatogenesis while minimizing systemic side effects can be challenging. Multiple targets are under investigation for male contraception, including inhibition of spermatogenesis and spermiogenesis, inhibition of sperm metabolism or signal transduction to impede motility or ability to fertilize, and reversible occlusion of the vas deferens to block sperm delivery, which are at various stages of preclinical and clinical development. ^{, ,} There is potential demand for male contraception, with 72% of cisgender men responding in 1 survey that they were very willing to use a male contraceptive, though their interest varied by type of method and potential side effects. Thus, it is essential to develop a variety of contraceptive technologies including pills, gels, injectables, and implants for men.

Multiple studies have been conducted on hormonal regimens to target the hypothalamic-pituitary-testes axis, and typically include a testosterone formulation to suppress spermatogenesis and a progestin to improve gonadotropin suppression and spermatogenesis while maintaining testosterone within physiologic ranges. Preliminary results from a Phase 2a trial of a combination gel containing testosterone and SA, applied daily to the arms and shoulders, demonstrated high efficacy. The gel was also safe, well tolerated, and reversible, which is promising for further investigation in a Phase 3 pivotal trial. Another hormonal option includes dimethandrolone undecanoate, a prodrug of dimethandrolone, which acts on both androgen and progesterone receptors. It has been studied as a daily oral pill and is under investigation in a Phase 1 trial as an injectable. ^{, ,}

There are multiple targets for nonhormonal male contraception. YCT529, an α-selective retinoic acid antagonist intended for oral daily use, is undergoing a Phase 1 clinical trial with a Phase 1 b/2a trial also planned. ^, YCT529 was 99% effective in mice and demonstrated reduction of sperm counts and reversibility by 4 to 6 weeks after stopping the medication. Inhibition of soluble adenylyl cyclase has also been investigated in mice as a target for on-demand male contraception through inhibiting sperm motility. ^, Reversible products to occlude the vas deferens are under development. The Bimek implantable device uses a reversible valve mechanism for occlusion. Another option for occlusion is with injectable polymers, including Vasalgel, a polymer of styrene maleic anhydride dissolved in dimethyl sulfoxide which may be reversible through flushing of the vas deferens, the Adam System, a hydrogel that liquifies at the end of its lifespan to be reversible, and reversible inhibition of sperm under guidance, a copolymer of styrene and maleic anhydride. ^,

Multipurpose Prevention Technologies

Multipurpose prevention technologies (MPTs) are products designed to target 2 or more sexual or reproductive health problems. External and internal condoms are examples of currently available MPTs that can protect against both pregnancy and STIs. Multiple MPTs targeting both pregnancy and STIs including human immunodeficiency virus (HIV) prevention are at various stages of preclinical and clinical development. An MPT product development database can be found at https://mpts101.org/ . These products include oral pills, vaginal rings, vaginal and rectal gels, fast-dissolving vaginal and rectal inserts, vaginal films, implants, injectables, and microarray patches. Immunocontraceptives containing antisperm monoclonal antibodies in conjunction with monoclonal antibodies against specific STIs such as HIV-1 and HSV-2 are also under investigation as MPT candidates. ^{, ,}

A dual prevention pill (DPP) containing an antiretroviral, tenofovir disoproxil fumarate/emtricitabine (TDF/FTC, or Truvada), and levonorgestrel/EE as a contraceptive, is being developed as a combination MPT in hopes of faster regulatory approval through combining 2 already approved products. DPP contains 21 tablets of levonorgestrel/EE with TDF/FTC and 7 tablets of TDF/FTC during what would typically be the placebo week of combined oral contraceptive pills. In focus group discussions, DPP was acceptable to potential users due to ease of use and access as well as possibility of covert use in situations where ability to negotiate condom use may be limited. DPP is also likely to be cost-effective in populations at higher risk for HIV.

There are multiple intravaginal MPT ring formulations under development. An extended duration 90-day matrix vaginal ring containing dapivirine, a non-nucleoside reverse transcriptive inhibitor, and levonorgestrel was evaluated in 2 Phase 1 trials and was found to be generally well tolerated with pharmacokinetic levels that exceeded concentrations in prior dapirivine ring efficacy studies and levonorgestrel-based contraceptives. However, frequent ring expulsions, slippages, and vaginal bleeding issues affected acceptability of this formulation. The product was reformulated as a core-sheath ring and is undergoing a Phase 1b trial, with study completion estimated in December 2024.

A 90-day vaginal ring containing tenofovir, a nucleotide analog reverse transcriptase inhibitor, and levonorgestrel is under development for HIV and pregnancy prevention. Two Phase 1 studies comparing a ring containing tenofovir only with a ring containing tenofovir/levonorgestrel found vaginal tenofovir concentrations for both rings exceeded the estimated threshold for HIV prevention. ^, Users of rings containing levonorgestrel/tenofovir in the 90-day trial met at least one surrogate marker of contraceptive efficacy, defined as anovulation, a cervical mucus score indicating poor cervical mucus quality, or abnormal sperm penetration assays. A Phase 2a study conducted in Kenya found tenofovir levels that exceeded the estimated threshold for HIV prevention. Levonorgestrel levels similarly exceeded estimated thresholds for levonorgestrel-based contraception. In vitro evaluations of cervicovaginal fluid in ring users demonstrated anti-HIV-1 and anti-HSV-2 activity. The tenofovir/levonorgestrel ring shows promise for multipurpose prevention against HIV, HSV-2, and pregnancy.

Other sexual and reproductive health problems include endometriosis and uterine fibroids. A combination daily oral product containing relugolix 40 mg, a gonadotropin-releasing hormone antagonist, estradiol 1 mg, and norethindrone acetate 0.5 mg is approved by the FDA as Myfembree for treatment of uterine fibroids and endometriosis for up to 24 months. The estradiol and norethindrone acetate provide add-back therapy to reduce hypoestrogenic symptoms. A Phase 3 study is ongoing to assess contraceptive efficacy of this combination product with study completion estimated in February 2026.