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Male Contraceptive Development:
Update on Novel Hormonal and
Nonhormonal Methods
Jill E. Long,
1*
Min S. Lee,
1
and Diana L. Blithe
1
BACKGROUND:Development of new methods of male
contraception would address an unmet need for men to
control their fertility and could increase contraceptive
options for women. Pharmaceutical research and devel-
opment for male contraception was active in the 1990s
but has been virtually abandoned. The Eunice Kennedy
Shriver National Institute of Child Health and Human
Development (NICHD) has supported a contraceptive
development program since 1969 and supports the ma-
jority of hormonal male contraceptive development.
Nonhormonal methods are also in development but are
at earlier stages.
CONTENT:Several hormonal male contraceptive agents
have entered clinical trials. Single-agent products being
evaluated include dimethandrolone undecanoate, 11

-
methyl-nortestosterone dodecyl carbonate, and 7
␣
-
methyl-19-nortestosterone. A contraceptive efficacy trial
of Nestorone
®
gel and testosterone gel in a single appli-
cation will begin in 2018. Potential nonhormonal meth-
ods are at preclinical stages of development. Many non-
hormonal male contraceptive targets that affect either
sperm production or sperm function have been identi-
fied. Targeted pathways include the retinoic acid path-
way, bromodomain and extraterminal proteins, and
pathways for Sertoli cell–germ cell adhesion or sperm
motility. Druggable targets include CatSper, the sperm
Na⫹/K⫹-exchanger, TSSK, HIPK4, EPPIN, and
ADAMs family proteins. Development of a procedure to
reversibly block the vas deferens (initially developed in
India in the 1980s) is undergoing early stage research in
the US under the trade name Vasalgel™.
SUMMARY:NICHD has supported the development of
reversible male contraceptive agents. Other organizations
such as the World Health Organization and the Popula-
tion Council are pursuing male contraceptive develop-
ment, but industry involvement remains dormant.
© 2018 American Association for Clinical Chemistry
The unintended pregnancy rate in the US is approxi-
mately 45% (1), despite a variety of contraceptive op-
tions available to women. Male condoms and withdrawal
are the only reversible contraceptive methods available to
men, with typical failure rates of 13% and 20%, respec-
tively (2). Studies indicate that ⬎50% of men would be
interested in using a reversible method, if available (3),
and many women would be willing to rely on their part-
ner to use a contraceptive (4). Unplanned pregnancy
rates could improve if both partners used a contraceptive
method or if men had more options to control their own
fertility.
Hormonal Male Contraception
Hormonal male contraceptive effectiveness has been es-
tablished (5). However, the search for the “male pill” has
been hindered by the lack of a safe, effective oral andro-
gen, which is a necessary component of the method. Hor-
monal methods in men use a feedback mechanism similar
to hormonal methods in women. In healthy men, testic-
ular testosterone concentrations are 40- to 100-fold
higher than serum testosterone concentrations. This high
intratesticular testosterone concentration is required for
spermatogenesis. Exogenous steroid hormone adminis-
tration, an androgen alone or in combination with a pro-
gestin or gonadotropin-releasing hormone agonist or an-
tagonist, suppresses testicular testosterone production
through feedback inhibition of the hypothalamic–
pituitary axis. Below a threshold amount of testicular
testosterone, sperm production does not occur. How-
ever, other androgen-dependent functions such as libido,
erection, ejaculation, and maintenance of muscle mass
are dependent on sufficient serum testosterone concen-
trations. Therefore, exogenous androgens must be ad-
ministered to maintain sufficient serum concentrations
to support those functions while keeping testicular tes-
tosterone below the threshold to initiate sperm produc-
tion. Studies using this approach have shown high rates
of severe oligozoospermia (⬍1 million/mL) or azoosper-
1
ContraceptiveDevelopmentProgram; Eunice KennedyShriverNational Institute ofChild
Health and Human Development, National Institutes of Health, Bethesda, MD.
* Address correspondence to this author at: 6710B Rockledge Drive, Room 3243,
Bethesda, MD 20892. E-mail jill.long@nih.gov.
Received August 2, 2018; accepted September 20, 2018.
DOI: 10.1373/clinchem.2018.295089
© 2018 American Association for Clinical Chemistry
Clinical Chemistry 65:1
153–160 (2019) Reviews
153
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mia (no sperm), resulting in high contraceptive efficacy
with few reported side effects (5, 6).
The challenge for developing the “male pill” is that
oral testosterone is cleared too rapidly to be effective as a
single daily dose regimen even in combination with a
progestin. Multiple doses of oral testosterone per day
would be impractical for contraception. Although 17-
methyl-testosterone has better oral bioavailability, it has
been associated with hepatotoxicity when used long
term. The Eunice Kennedy Shriver National Institute of
Child Health and Human Development (NICHD)
2
has
supported the development of new androgens that also
bind to progesterone receptors and potentially may serve
as single-agent male contraceptive drugs (7). Two lead
candidates are in clinical development: dimethandrolone
undecanoate and 11

-methyl-nortestosterone dodecyl
carbonate (8, 9). These drugs are not susceptible to 5
␣
-
reduction, a characteristic that may be beneficial to pros-
tate health and may lessen male pattern baldness. When
administered orally or intramuscularly, dimethandrolone
undecanoate is hydrolyzed to the active drug dimeth-
androlone, a novel derivative of 19-nortestosterone that
binds to both androgen and progesterone receptors. Di-
methandrolone undecanoate has been evaluated in early
phase I clinical trials in the NICHD’s Contraceptive
Clinical Trials Network and was well tolerated (10).A
first-in-man clinical trial of 11

-methyl-nortestosterone
dodecyl carbonate is underway in the Contraceptive
Clinical Trials Network. Longer term evaluation of pro-
gestagenic androgens is necessary to determine if the
drugs are safe and can effectively suppress sperm produc-
tion. These clinical evaluations will demonstrate if either
of these drugs can be used as a single-agent hormonal
contraceptive for men.
Another synthetic androgen, 7
␣
-methyl-19-
nortestosterone (MENT), is currently being evaluated
as a possible male contraceptive (11). MENT is not a
substrate for 5
␣
reduction and may provide selective
sparing of the prostate while supporting other androgen-
dependent functions. Initial evaluations of MENT im-
plants to suppress sperm production were comparable to
initial studies with testosterone, with about two-thirds of
men showing dose-dependent spermatogenesis suppres-
sion (12). Improvements of the MENT implant result-
ing in sustained concentrations of MENT release are in
development but require further validation in clinical
trials.
Although an effective oral testosterone product has
not yet been developed, transdermal testosterone gels or
an injectable androgen may provide an alternate dosing
regimen. Testosterone gels are widely used in the US to
treat hypoandrogenism. Combining testosterone gel and
injections of the progestin depomedroxyprogesterone ac-
etate, used for female contraception, resulted in effective
sperm suppression in 90% of participants in one trial
(13). Notably, this method involved 2 Food and Drug
Administration–approved products, albeit they were used
for off-label indications.
Of the few hormonal male contraceptive effective-
ness trials, the most recent was a phase II, multisite inter-
national clinical trial sponsored by the World Health
Organization and CONRAD. The study evaluated the
contraceptive efficacy and safety of separate intramuscu-
lar injections, at 8-week intervals, of a long-acting pro-
gesterone, norethisterone enanthate, and a long-acting
androgen, testosterone undecanoate (14). Couples (n ⫽
320) were enrolled, with 266 entering the efficacy phase.
Per the recommendation of an external safety review
committee, the study was terminated early because of the
frequency of reported mood changes, depression, pain at
the injection site, and increased libido. However, the
combined method failure rate, including sperm nonsup-
pression by the end of the suppression phase, sperm re-
bound during the efficacy phase, and pregnancy during
the efficacy phase, was 7.5%. Importantly, ⬎75% said
they would be willing to use the method if it were
available.
Taking advantage of the transdermal effectiveness of
testosterone, another regimen in development includes
daily applications of Nestorone gel and testosterone gel.
Use of Nestorone gel (8 mg) and testosterone gel (100
mg) suppressed sperm concentration to ⬍1 million/mL
or to azoospermia in 89% of men compared to only 23%
of men using testosterone gel and a placebo gel (15).
Suppression of serum gonadotropins (luteinizing hor-
mone and follicle-stimulating hormone) occurred rap-
idly. Gonadotropin hormone concentrations that were
⬎1 IU/L after 4 weeks of treatment predicted treatment
failure (sperm concentration ⬎1 million/mL) with 97%
diagnostic sensitivity (16). Most failure was due to in-
consistent or nonuse of the products rather than to non-
response to the drug regimen. When asked about accept-
ability of the regimen, over half of participants reported
being satisfied or extremely satisfied with this method of
contraception (17). A contraceptive efficacy study to
evaluate combined Nestorone and testosterone in a single
gel preparation for use as a primary method of contracep-
tion in couples began enrollment in the Contraceptive
Clinical Trials Network in 2018.
2
Nonstandardabbreviations:NICHD, EuniceKennedyShriver NationalInstituteof ChildHealth
and Human Development; MENT, 7
␣
-methyl-19-nortestosterone; RAR
␣
, retinoic acid recep-
tor
␣
; RA, retinoic acid; BDAD, bisdichloroacetyldiamine analog; ALDH, aldehyde dehydroge-
nase; BRDT, bromodomain testis-specific protein; BET, bromodomain and extraterminal;
ABHD2,
␣
/

hydrolase domain-containing protein 2; sNHE, sperm Na+/H+-exchanger;
TSSK, testis-specific serine/threonine kinases; HIPK4, homeodomain-interacting protein ki-
nase4;EPPIN, epididymalpeptidase inhibitor; ADAMs,a disintegrin andmetalloproteinases;
ADAMTS, ADAMs with thrombospondin motifs.
Reviews
154 Clinical Chemistry 65:1 (2019)
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Hormonal male contraceptive methods have proven
effective. Long-term safety will need to be demonstrated
before any method would be considered for regulatory
approval. Because men do not face the medical risks as-
sociated with pregnancy and childbirth, any systemic
product for men must have a strong safety profile. The
goal of identifying additional health benefits for male
methods is especially attractive. Realistically, it will be
several years before a product could reach the market
because long-term trials with a sufficient numbers of cou-
ples are required. Additionally, pharmaceutical invest-
ment will be required to achieve that goal.
Nonhormonal Male Contraception
In contrast to hormonal male contraception, in which
the mechanism of action is to suppress testicular tes-
tosterone production through feedback inhibition of
the hypothalamic–pituitary axis to stop sperm produc-
tion, the rationale behind the nonhormonal contra-
ceptives is to avoid the hypothalamic–pituitary axis, po-
tentially avoiding some side effects associated with
hormones. Nonhormonal male contraceptive research
involves targeting proteins that affect either sperm pro-
duction or sperm function. Although nonhormonal con-
traceptive targets do not target the hypothalamic–pitu-
itary axis, off-target side effects should still be minimized.
This is largely contingent on specificity and potency of
inhibitors for the target protein. Nonhormonal male
contraceptive development is still in the preclinical
phase; however, within the past decade or so, increasing
efforts with iterative screening, structural biology, com-
putational modeling, and designer chemistry have been
employed to move forward several nonhormonal male
contraceptives.
First studied and recognized in male rats, vitamin A
(retinol) deficiency and its physiologically active metab-
olite, all-transretinoic acid, have long been recognized for
their role in male sterility (18). Retinoic acid is required
for normal spermatogenesis. Additionally, retinoic acid
receptor
␣
(RAR
␣
) mouse knockout models display phe-
notypic sterility in male mice. The retinoic acid (RA)
pathway, including conversion of retinol to retinal and
finally to RA, provides places where inhibitors or antag-
onists can be applied to stop RA synthesis and thereby
stop spermatogenesis. Suppression of spermatogenesis
involving the RA pathway was demonstrated with a bis-
dichloroacetyldiamine analog (BDAD) (19). In a clinical
study, one BDAD, known as WIN18,446, was used to
treat over 60 men for 1 year. The drug was well tolerated
and efficacious at inhibition of spermatogenesis. How-
ever, consumption of alcohol induced a severe disulfiram
reaction, causing termination of development of the
drug. The disulfiram reaction caused by BDADs is due
to off-target inhibition of a liver enzyme, aldehyde
dehydrogenase-2 (ALDH2). This enzyme detoxifies al-
dehyde during alcohol metabolism and inhibition by
BDADs produced toxic aldehyde accumulation. A differ-
ent aldehyde dehydrogenase subfamily, ALDH1A, is in-
volved in the synthesis of RA, and a testis-specific mem-
ber includes ALDH1A2. Covalent and noncovalent
small-molecule inhibitors of ALDH1A2 have been devel-
oped recently. Ternary x-ray cocrystal structures of the
inhibitors provide the structural framework for design of
potent and selective inhibitors of ALDH1A2 (20).
An alternative approach in the RA synthetic path-
way is inhibition of RAR
␣
.AnRAR
␣
variant is essential
for spermatogenesis, and mouse knock-outs show pheno-
typic infertility. A study with the pan-retinoic acid recep-
tor antagonist BMS-189453 demonstrated reversible
spermatogenesis inhibition in a mouse model (18).
Structure-based drug design, with iterative screening, is
being employed to develop potent specific antagonists to
inhibit RAR
␣
activity in the RA synthetic pathway to
inhibit sperm production.
Another nonhormonal target is bromodomain
testis-specific protein (BRDT), a subfamily of bromodo-
main and extraterminal (BET) proteins, which consists
of 4 members: BRD2, BRD3, BRD4, and BRDT.
Testis-specific BRDT is critical for chromatin remodel-
ing during spermatogenesis (21). Mice with homozygous
BRDT null mutations are viable, but male animals are
sterile (22). Validation of BRDT as a nonhormonal male
contraceptive target was further strengthened by pharma-
cological inhibition of BRDT. A study showed that JQ1,
a small-molecule inhibitor of BRDT, was able to cross
the blood–testis barrier and cause complete, reversible
contraceptive activity in male mice (20). Although effec-
tive for contraception, JQ1 had off-target binding to
other BRD proteins. Efforts are underway with different
chemical scaffolds in discovery and optimization of new
inhibitors of BRDT. A study entailing virtual screening,
analytical testing, structure–activity relationship evalua-
tion, and compound optimization via x-ray cocrystal
have resulted in different chemical scaffolds with potent
BRDT activity (23). Each BET protein has 2 bromodo-
main modules, and the second module (BD2) may be a
target for enhancing specificity. Focused library screen-
ing and subsequent optimization has produced potent
BET inhibitor candidates selective for BD2 (24).
Mechanistically different drug candidates that target
Sertoli cell–germ cell adhesion and cause release of im-
mature spermatids from the seminiferous epithelium
have been identified. CDB-4022, an indenopyridine, has
been shown to effect inhibition of mature sperm produc-
tion in primates and stallions. Cessation of the drug treat-
ment brings about full reversibility of sperm production
with no apparent side effects (25, 26). Another series of
drug candidates targeting Sertoli cell–germ cell interac-
tion are the indazole carboxylic acid derivatives gamenda-
Review of Male Contraceptive Development Reviews
Clinical Chemistry 65:1 (2019) 155
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zole, H2-gamendazole, and adjudin. These analogs have
shown to affect fertility in animal models. In particular,
rats treated with oral doses of H2-gamendazole showed
inhibition of fertility (27). Although at low doses the
drug effect was reversible, at higher doses the fertility
effect was irreversible. The challenge of inhibitors cross-
ing the blood–testis barrier is demonstrated by the diffi-
culty in targeting Sertoli cells. To enhance specificity,
adjudin was conjugated to a recombinant follicle-
stimulating, hormone-binding fragment to target the tes-
tis germ cell–Sertoli cell junction (28). The increase is
specificity was offset by the reduction of the oral bioavail-
ability caused by the peptide. In general, for this series of
molecules, safety and reversibility should be demon-
strated in higher mammals.
There are numerous ion channel and kinase protein
targets that affect sperm motility. Many of these proteins
are produced in the tail region of the sperm. Ion channels
such as CatSper (a calcium ion channel) and KSper (a
potassium ion channel) are sperm specific and they are
required in male fertility (29). Male infertility profile
without apparent systemic effects were displayed in gene
mutations and deletions in animal models. An in vitro
study with HC-056456, an inhibitor of the calcium ion
channel, demonstrated that the drug prevented hyperac-
tivation of sperm (30). A sperm-specific potassium chan-
nel, KCNU1, controls calcium entry through CatSper.
Genetic deletion of SLO3 causes male infertility in mice
(31).
CatSper is activated by progesterone and prostaglan-
dins through a nonclassical binding domain, causing
sperm tail hyperactivation. Under normal function,
CatSper is activated in an unconventional pathway in-
volving progesterone binding and activating
␣
/

hydro-
lase domain-containing protein 2 (ABHD2), causing the
depletion of endocannabinoid 2-arachidonoylglycerol
from plasma membrane in spermatozoa. The 2-
arachidonoylglycerol inhibits CatSper, and the removal
by ABHD2 causes calcium influx leading to sperm acti-
vation (32). Physiologically, the cumulus–oocyte com-
plex likely provides the source of progesterone after it
leaves the ovary, enters the fallopian tube, and migrates
toward the ampulla. Sperm enters the tubal isthmus
through the uterotubal junction and forms a reservoir
(33). Each ejaculate contains millions of sperm, but only
a few hundred or less bind to the wall of the oviduct and
undergo capacitation (34). Sperm can remain viable in
the isthmus for several days until progesterone and other
triggers signal them to swim toward the tubal ampulla
where fertilization may occur. A recent study demon-
strated that the steroidal inhibitor RU1968 causes dys-
function of CatSper’s progesterone-mediated motility re-
sponse. The inhibitor is nontoxic to human sperm and
inhibits hSLO3 with approximately 15-fold lower po-
tency than CatSper (35). It is unclear if this approach
would be more appropriate for female use as it affects
progesterone function in the oviduct, but the targets
remain an area of nonhormonal contraceptive research
interest.
The soluble adenylyl cyclase and a sperm Na⫹/H⫹-
exchanger Slc9c1 form a complex critical for sperm mo-
tility (36). Mouse knockout of Slc9c1 displays infertility
phenotype, making the exchanger another potential
sperm-specific target for male contraception. In particu-
lar, Slc9a8
⫺/⫺
male mice are infertile owing to disruption
in acrosome formation (37). The NHE in human sperm
is mainly localized to the principal piece of the tail, and
the production pattern suggests implication in the regu-
lation of sperm motility (38). The Na⫹/K⫹-ATPase
(sodium pump) is important in sperm motility and ca-
pacitation (39). These ion channels are found in many
tissues, but the
␣
4-subunit of the Na⫹/K⫹-ATPase is
sperm specific and appears to be necessary for sperm
function. The
␣
4-subunit knockout male mice are com-
pletely infertile (40). One of the first known inhibitors
for Na⫹/K⫹pumps are cardenolide analogs. They have
been used clinically to treat congestive heart failure.
Ouabain, a cardenolide analog, has higher affinity for the
Na⫹/K⫹-ATPase
␣
4 isoform than the other somatic
forms,
␣
1,
␣
2, and
␣
3, in both mice and humans. Opti-
mization using the ouabain scaffold as a starting point
may yield derivatives with specificity for the
␣
4 subunit
(41, 42). Ouabain derivatives modified at the glycone
(C3) and the lactone (C17) domains show picomolar
inhibition for the
␣
4 isoform with an excellent selectivity
profile against
␣
1,
␣
2, and
␣
3. Additionally, decrease in
sperm motility in vitro and in vivo was demonstrated for
the new ouabain triazole analogs (43).
Several testis-specific serine/threonine kinases (TSSK)
are important for spermatogenesis and function. In the
human kinome, the TSSKs belong to a 5-member, testis-
specific serine/threonine kinase family: TSSK1, TSSK2,
TSSK3, TSSK4 (also known as TSSK5), and TSSK6.
Male infertility is the phenotype displayed for the double
TSSK1/TSSK2 knockout mice, indicating a critical role
for TSSK1 and TSSK2 in spermiogenesis (44, 45). Pro-
tein production of stable and enzymatically active recom-
binant human TSSK2 represents a key achievement in
progress toward targeting TSSKs as valid male contracep-
tive target proteins (46). Additionally, evidence from
mutation screening in 494 patients with azoospermia or
severe oligozoospermia in comparison with those in 357
fertile controls indicate single-nucleotide polymorphisms
of TSSK2, associated with idiopathic infertile men with
3
Genes: Slc9c1, solute carrier family 9, subfamily C (Na+-transporting carboxylic acid
decarboxylase), member 1; Slc9a8, solute acarrier family 9 sodium/hydrogen ex-
changer), member 8; TSSK2, testis specific serine kinase 2.
Reviews
156 Clinical Chemistry 65:1 (2019)
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impairment of spermatogenesis (47). High-throughput
screening of TSSK2 assays have revealed sub-100 nano-
molar inhibitors that show promise for targeting the
TSSKs with small-molecule inhibitors (48).
The homeodomain-interacting protein kinase 4
(HIPK4) plays a role in later stages of sperm maturation
and is another potential nonhormonal target under de-
velopment (49). HIPK4 knockout mice have impaired
spermatogenesis but are otherwise healthy.
A sperm surface protein EPPIN (epididymal pepti-
dase inhibitor) is another potentially druggable contra-
ceptive target. A recent study has shown that intravenous
infusion of a small-molecule inhibitor of EPPIN, EP055,
resulted in dramatic reduction of sperm motility to ap-
proximately 20% of pretreatment levels in a monkey
model. EP055 is thought to cause a rapid decrease in
sperm internal pH and calcium level, affecting sperm
motility (50).
Numerous protein targets that affect sperm function
have been identified. The challenge remains for these
nonhormonal proteins targeting sperm function to be
developed into effective and reversible contraceptive
agents that can safely and permanently inhibit function
of the sperm in the female reproductive tract. Several
members of a disintegrin and metalloproteinases
(ADAMs) family of proteins are produced exclusively or
predominately in the testis or epididymis (51). Addition-
ally, related members of ADAMs with thrombospondin
motifs (ADAMTS) are also proposed to participate in
sperm–egg adhesion (52). An ADAMTS-like protein
from sea urchin is proposed to mediate species-specific
sperm–egg adhesion (53). A systematic study to identify
sperm membrane alloantigens found ⬎20 potential
unique sperm membrane and 5 sperm raft proteins.
Among these, ADAM1, ADAM2, and ADAM3 were the
dominant sperm membrane alloantigens (54). Further,
in ADAM3 knockout mice, sperm were unable to enter
the oviduct (55). However, it is unclear if human sperm
have the same requirement for ADAM3. Numerous
ADAM proteins form complexes that are required for
sperm– egg binding (51). Additionally, ADAM family of
proteases are increasingly the targets for new therapies in
many areas of medicine (56). Sperm–egg binding is ex-
emplified by Izumo1, a sperm surface protein that binds
to JUNO (Izumo1R) on the egg, leading to sperm–egg
fusion (57).
Gossypol is a polyphenolic aldehyde-containing
compound isolated from the cotton plant (58, 59). The
infertility profile of gossypol was discovered in rural areas
of China when the farmers begin to press uncooked cot-
ton seeds for oil in the 1950s and 1960s. The eventual
outcome of consuming raw untreated oil resulted in
infertility for both women and men. Subsequently, a
gossypol-free diet resulted in eventual recovery for
women. However, some men did not recover from their
infertility and impotency. The findings indicated that the
rates of recovery and permanent infertility were associ-
ated with quantity and duration of cotton oil consump-
tion (58). This information led to the idea that gossypol
could be used as a male contraceptive. Thus, clinical stud-
ies for gossypol were initiated in China in the 1970s and
1980s as a male contraceptive. In total, ⬎8000 volun-
teers participated in these studies. Gossypol, as male con-
traceptive, was highly efficacious; however, the narrow
therapeutic window, frequent association with hypokale-
mia, and irreversible sterility caused termination of fur-
ther clinical development (60, 61).
Extract from Tripterygium wilfordii Hook. f., com-
monly called thunder god vine, has been used in Chinese
herbal medicine for many years. Further, for ⬎50 years,
refined extract has been used to treat rheumatoid arthri-
tis, chronic nephritis, chronic hepatitis, and various skin
disorders (62, 63). Triptolide, a major component of the
extract, belongs to the class of chemicals called diterpene
epoxides (64). The first indication of the potential con-
traceptive effect of triptolide was gleaned from rheuma-
toid arthritis patients. The rheumatoid arthritis patients
treated with the extract showed necrospermia or azoo-
spermia characteristics (63, 65, 66). Subsequent studies
in rats showed that T. wilfordii extracts containing diter-
pene epoxides cause infertility in male rats, with a severe
decrease in epididymal sperm count and motility
(62, 63, 66–70). Similar to gossypol, prolonged expo-
sure was associated with irreversible infertility in rodents
(68, 70). However, triptolide’s immunosuppressive
properties likely would prevent its long-term use and its
development as a contraceptive.
A commonly used plant to prepare jamu, an Indo-
nesian traditional medicine, Justicia gendarussa has been
used as a male contraceptive in Papua. Additionally, this
plant is used as an antiinflammatory, antibacterial, and
antifungal agent and is used to treat a variety of ailments
including arthritis and cancer. Gendarussa is a com-
monly used term when referring to the extract of J. gen-
darussa for male contraception. In particular, gendarusin
A and B, flavonoid scaffold analogs, are thought to be the
active metabolites responsible for eliciting the contracep-
tive effect (71), possibly by decreasing human sperm hy-
aluronidase activity. An unpublished clinical trial per-
formed in Indonesia reported contraceptive efficacy of
Justicia gendarussa plant extract if ingested by the male part-
ner daily for at least 20 days before having intercourse during
the female’s ovulatory period. Fertility was restored within
30 days after last usage, and minimal side effects were re-
ported. Additional study on its mechanism of action and
evaluation of longer duration of use will be required before
any regulatory approval (unpublished observations).
Using a local vs systemic approach to male contra-
ception, development of a nonhormonal method to re-
versibly block the vas deferens was begun in the late
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Clinical Chemistry 65:1 (2019) 157
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1970s in India. The procedure is called RISUG (revers-
ible inhibition of sperm under guidance), in which the
polymer styrene maleic anhydride is mixed with the sol-
vent dimethyl sulfoxide and injected into the vas deferens
(72). The polymer was thought to damage sperm, mak-
ing them ineffective. The procedure was used in rats,
monkeys, and in the first human in 1989. By 2000,
RISUG was evaluated in a phase III clinical trial in India
with promising results. However, an inspection of the
Indian facilities by the World Health Organization pro-
duced concerns that studies were not done according to
international standards, and further development was
stymied. Intellectual property rights to RISUG were ac-
quired by the Parsemus Foundation, a nongovernmental
organization, in 2010, which then developed Vasalgel,
also a styrene maleic anhydride acid polymer dissolved in
dimethyl sulfoxide. Vasalgel does not claim any effect on
the sperm and is purported to act as a mechanical barrier
to sperm passage. It is thought that sperm flow can be
restored by flushing the vas with an injection of sodium
bicarbonate solution. The Parsemus Foundation has per-
formed preclinical studies in rabbits and monkeys
(73, 74 ) and intends to begin trials in humans in 2019 or
2020. A competitor to Parsemus, Contraline, is develop-
ing a hydrogel called Echo-V that can be injected into the
vas deferens to block the flow of sperm but not other
fluids (75). The gel ideally could be dissolved when the
man is ready to restore fertility.
Conclusion
Although some nonhormonal natural products have
gone into the clinic, nonhormonal male contraceptives
are in early stages of development. In addition to the
protein targets and small-molecule inhibitors described
above, active research is ongoing for nonhormonal con-
traceptive target discovery and validation. As exemplified
above, numerous laboratories are engaged in discovery
and optimization of small-molecule inhibitors. It is
hoped that some of these small-molecule contraceptive
agents would enter preclinical development and further
into clinical development in the near future.
A variety of new contraceptive methods are under
development for men. The introduction of an effective
reversible male contraceptive method has the potential to
dramatically reduce unplanned pregnancy rates. It would
likely represent a new market opportunity rather than
creating a significant reduction in the use of existing fe-
male contraceptive methods. How a possible risk to one
individual may be mitigated by prevention of potential
health consequences in another individual provides an
interesting regulatory consideration for the evaluation of
systemic male contraceptive agents. At the current pace
of drug development, regulatory approval for a new male
product in the US likely would not occur until at least
2030.
Author Contributions: All authors confirmed they have contributed to
the intellectual content of this paper and have met the following 4 require-
ments: (a)significant contributions to the conception and design, acquisi-
tion of data, or analysis and interpretation of data; (b)drafting or revising
the article for intellectual content; (c)final approval of the published article;
and (d)agreement to be accountable for all aspects of the article thus
ensuring that questions related to the accuracy or integrity of any part of the
article are appropriately investigated and resolved.
J. Long, administrative support.
Authors’ Disclosures or Potential Conflicts of Interest:Upon man-
uscript submission, all authors completed the author disclosure form. Dis-
closures and/or potential conflicts of interest:
Employment or Leadership: D. Blithe, National Institutes of Health,
US Government.
Consultant or Advisory Role: None declared.
Stock Ownership: None declared.
Honoraria: None declared.
Research Funding: None declared.
Expert Testimony: None declared.
Patents: None declared.
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