Present and future contraception: does discovery of targets lead to new contraceptives?

Abstract

Although many highly effective methods of reversible contraception are available, high rates of unintended pregnancy and abortion provide evidence that current methods do not meet the needs of all couples. In recent years, a number of highly specific targets have been identified in key pathways that regulate the development of male and female gametes. Support for development of novel approaches has moved from industry to governmental and foundation funders. Continued public funding will be needed to move promising leads into clinical trials.

Keywords:

• contraception
• female
• male
• targets

We and our offspring are living in the era of peak population. World population eclipsed 7 billion in 2012 and (if we are fortunate) will peak at somewhere over 11 billion before gradually stabilizing in the next millennium [1]. Although progress has been made, the total fertility rate (TFR) globally remains above 2.1 today, and we have a long way to go to reach this goal. However, to do otherwise is unthinkable. At the current global TFR of 2.6, world population would be expected to surpass 25 billion by 2150 [1]. There is no question that earth cannot support this number of humans. Voluntary family planning represents the most humane option for our collective future.

Since the US approval of the combined oral contraceptive in 1960, there has been considerable progress made in the understanding of pathways essential to the development of female and male gametes, their interaction resulting in fertilization and in the attachment and progression of the early embryo. Strategies to prevent pregnancy can be classified as contraceptive when they act to prevent fertilization, contragestive when they interfere with implantation and abortifacient when they disrupt the implanted embryo of fetus. Given that politics influence the behavior of regulatory authorities, funders and pharmaceutical companies, new product development will likely favor contraceptive mechanisms.

Except for barrier methods and copper intrauterine devices, current contraceptive strategies rely on hormonal effects. Currently only female hormonal methods such as the combination pill, patch and ring, the progestin-only pill and the levonorgestrel intrauterine device are approved by regulatory authorities. Although male hormonal methods using testosterone or other androgens alone or in combination with a progestin or gonadotropin-releasing hormone agonist have completed clinical trials, none have been approved or marketed [2,3]. The Population Council has developed implants delivering 7 α-methyl-19-nortestosterone, a potent synthetic androgen that is prostate-sparing as it does not undergo 5 α-reduction [4]. Given that male participation in contraception is ∼ 30%, according to recent estimates of the use of vasectomy, condoms and withdrawal from the National Survey of Family Growth, the absence of a commercially available male hormonal agent may reflect more of a lack of interest by industry than by men [5]. But to be fair, the regulatory burden for approval of a male product is challenging, as the potential risks of use are not offset by the major health benefit (reduction in pregnancy-associated complications) seen in women using hormonal methods.

Although the multiple systemic effects of hormonal therapy leads to uncommon but serious adverse events in some users, and a variety of minor side effects in others, the overall experience with female hormonal approaches demonstrate they are safe and highly effective [6]. Recent refinements in female hormonal contraceptives include the use of ligands with more neutral metabolic profiles. One example is nestorone, a 19-nor derivative of progesterone with potent progestational activity but no androgenic, glucocorticoid or estrogenic activity in vivo [7]. The Population Council, supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), has completed Phase III clinical trials of a nestorone/ethinyl estradiol-releasing vaginal ring that can be used for 1 year without replacement. Another refinement has been the substitution of estradiol for ethinyl estradiol in two combined pills (estradiol valerate/dienogest; estradiol/nomegestrol acetate). The use of estradiol is also under investigation in combination with vaginal ring delivery systems. A better progestogen-only pill containing desogestrel that effectively suppresses ovulation is available in Europe, but not in US. The selective progesterone-receptor modulator ulipristal acetate (UPA) was developed by the NICHD and is currently an approved agent for use as an emergency contraceptive pill. The Population Council, HRA Pharma and NICHD have investigated UPA delivered through a vaginal ring and as a daily pill for regular contraception. Nonetheless, concerns about safety of hormonal contraception worldwide contribute to non-use of these highly effective methods and this likely results in unintended pregnancy, abortion and unwanted birth. The push for the discovery and development of highly selective targets is largely driven by this perception.

Over the past few decades, much effort has been directed toward discovery of highly selective targets involved in spermatogenesis and oocyte maturation. On the male side, the multiple steps involved in sperm production, transport and motility offer a variety of contraceptive opportunities. Several highly selective targets have been identified. CatSper (Cation channel of Sperm) is a unique sperm-associated calcium channel that is an essential regulator of sperm capacitation and motility [8]. Mutations in the genes coding for CatSper are associated with unexplained male infertility [9]. The search for highly selective agents that block CatSper is underway. Another leading category of potential male contraceptives are agents that disrupt the blood–testes barrier. H2-gamendazole, a lonidamine derivative, is the lead compound in this category, with reversible inhibition of spermatogenesis demonstrated in rodents and nonhuman primates and toxicology evaluations are in progress to clear the way for early stage clinical trials [10]. Adjudin is another lonidamine derivative that functions as a contraceptive by disrupting the adhesion of spermatids to Sertoli cells, causing premature spermiation and infertility [11]. The drug rapidly and reversibly inhibits fertility in rodents, but concerns of liver toxicity have hampered development [12]. Importantly, serum testosterone, follicle-stimulating hormone and luteinizing hormone (LH) levels do not change with either lonidamine derivative [13]. Inhibition of testicular retinoic acid biosynthesis provides another therapeutic option [14]. High-throughput screening has identified several promising selective inhibitors of the alcohol dehydrogenase 1a2 enzyme [15]. All of these developments have received key funding from the Contraceptive Discovery and Development Branch (CDDB) of NICHD.

Potential highly selective novel targets for female contraception include inhibitors of oocyte maturation, cumulus-expansion and follicle rupture. Factors that specifically prevent or mistime oocyte maturation without affecting other aspects of the menstrual cycle represent attractive non-hormonal contraceptive choices, as the mechanism is unequivocally preconceptional. Whereas cytoplasmic maturation of the oocyte occurs during the progression from resting follicle to preovulatory follicle, the initiation of nuclear maturation of the oocyte is dependent on the mid-cycle LH surge [16] and is marked by the breakdown of the germinal vesicle that is associated with decreased levels of cAMP and increased activity of M-phase promoting factor (MPF) [17]. Years of basic discovery have yielded two key targets: PDE3A plays a critical role in the degradation of intra-oocyte cAMP, and inhibitors of PDE3 prevent oocyte maturation; and WEE2, an oocyte-specific kinase, is a key regulator of MPF and meiotic events downstream of cAMP. MPF promotes M-phase entry in both mitotic and meiotic cell cycles [18]; WEE family members maintain MPF in an inactive state. Notably, WEE2 is specific to the oocyte and regulates MPF activity during oocyte meiotic maturation and fertilization. Work in our laboratory funded by NICHD has demonstrated that the PDE3 inhibitor ORG 9935 prevents primate oocyte maturation in vitro [19] and in vivo [20,21], and acts as a contraceptive in regularly cycling female macaques [22], but that poor drug bioavailability and non-target toxicity limit the practicality of this agent. More recently, we confirmed a role of cGMP, a natural inhibitor of PDE3, in the maintenance of meiotic arrest, and experiments are in progress to determine whether combinations of PDE inhibitors could be administered at doses that would be tolerated with minimal side effects. Our work in monkeys has also confirmed evidence from rodents that WEE2 is essential for exit from metaphase II following fertilization. Detailed evaluation of the structure and chemistry of the WEE2 protein and high-throughput target screening are underway to identify potential inhibitors.

Building on studies that have demonstrated a critical role of prostaglandin E2 in follicle rupture and cumulus expansion, specific prostaglandin E receptor (PTGER) antagonists have been tested for contraceptive potential. Administration of the investigational PTGER2 antagonist BAY06 to fertile cynomolgus macaques in breeding harems resulted in a reversible contraceptive effect [23]. The search for follicle-specific proteases involved that can be targeted to prevent follicle rupture is ongoing [24]. Similar to inhibitors of meiosis, these pathways exert a contraceptive effect without affecting menstrual cyclicity.

Declaration of interest

The author serves as a paid consultant for HRA Pharma; Bayer Healthcare; Merck; Agile Pharm; the Population Council; AbbVie; Evofem: ContaMed; Teva and MicroChips. He has received research support from Bayer Healthcare; Merck; Agile Pharm; the Population Council; AbbVie; Evofem and ContaMed. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.