FERTILITY AND STERILITY威

VOL. 80, NO. 1, JULY 2003

Copyright ©2003 American Society for Reproductive Medicine
Published by Elsevier Inc.
MODERN TRENDS
Printed on acid-free paper in U.S.A. Edward E. Wallach, M.D.
Associate Editor

Development of methods of male

contraception: impact of the World Health
Organization Task Force
Geoffrey M. H. Waites, Sc.D.
Institute of Reproductive Medicine, University of Münster, Münster, Germany and ANZAC Research Institute,
University of Sydney, Sydney, New South Wales, Australia

Objective: To give an historical record of the research of the World Health Organization (WHO) Task Force
to develop methods of male contraception; to examine the social, political, medical, pharmaceutical, funding,
and other factors that influenced progress; and to suggest reasons why such methods are only now becoming
available.
Design: Review of basic and clinical research over 30 years.
Setting: Task force of a multinational agency and collaborating agencies.
Conclusion(s): Through the involvement of many international scientists, the WHO Task Force has uniquely
contributed to the exploratory phases of the research in male contraception and by its multicenter contraceptive
efficacy studies has accelerated progress towards the ideal hormonal method. Despite an adverse climate
involving social and political attitudes, funding constraints, and pharmaceutical industry hesitations, WHO
formed coalitions with governments and international agencies to sustain research with results that apply to
men in culturally diverse populations and thereby to influence activities across the whole range of global
reproductive health and family planning. (Fertil Steril威 2003;80:1–15. ©2003 by American Society for
Reproductive Medicine.)
Key Words: World Health Organization, male contraception, clinical trials, social factors, reproductive
health

This review provides an historical record of By including contraceptive efficacy studies in

Received January 21,
2003; revised and
accepted January 21,
2003.
Reprint requests: Geoffrey
Waites, Sc.D., Route des
Cheneviers, 01630 St. Jean
de Gonville, France (E-mail:
gmhw@mail.usyd.edu.au).
0015-0282/03/$30.00
doi:10.1016/S0015-0282(03)
00577-6
the scientific, social, and political climate sur-
rounding the research and development of
methods of family planning for men. The focus
reflects the experiences of the author concern-
ing the manner and means by which this activ-
ity was undertaken by a multinational agency,
the World Health Organization (WHO). In ad-
dition, it offers explanations as to why phase III
clinical trials of methods based on hormonal
suppression of sperm production are only now
being undertaken, when methods for ovarian
suppression have been available to women for
more than 40 years.
One might have expected that the common
features of pituitary endocrine control of the
ovary and testis, whereby gonadotropin with-
drawal switches off the function of both go-
nads, would have led to the parallel develop-
ment of such methods in both sexes. That this
did not happen has been the subject of much
discussion and will be explored in this review.
its strategic planning, the WHO Task Force
greatly accelerated the search for the ideal hor-
monal method. Although not yet perfect, male
hormonal contraception is emerging as an in-
tramuscular regimen, which avoids the first-
pass liver exposure of oral medications, is a
format better accepted in some cultures, and
satisfies concerns about male compliance in
other cultures (1–3).
WHO AND THE GENESIS OF
RESEARCH ON MALE
FERTILITY REGULATION
The role of WHO in the research in family
planning methods has to be considered against
the background of the climate of world opinion
in the 1950s and 1960s. The World Health
Organization was severely criticized when pi-
lot studies on the introduction of the rhythm
method in urban and rural populations were

1
undertaken in 1951 at the request of India. Furthermore,
when it was suggested in 1953 that WHO should participate TABLE 1
in the World Population Conference being planned by the Members of the Steering Committees, 1973–1979.
United Nations, some member states even threatened to
leave WHO if it pursued activities in family planning and Member (Country) Specialty
population. As Dr. Alex Kessler, the charismatic first direc-
Paulsen CA (USA), Chairman Reproductive endocrinologist
tor of the WHO Special Programme of Research, Develop- Arslan M (Pakistan) Primatologist
ment, and Research Training in Human Reproduction Bain J (Canada) Reproductive endocrinologist
(HRP), stated, “for the next decade the subject of family Bedford JM (USA) Sperm maturation, epididymis
planning was to remain a taboo in WHO.” In 1962, the Chulavatnatol M (Thailand) Sperm biochemist
Diczfalusy E (Sweden) Reproductive endocrinologist
Director-General of WHO (Dr. Marcelino Candau, Brazil),
Franchimont P (Belgium) Inhibin endocrinology
in a speech to the Fourth World Congress on Fertility and Gombe S (Kenya) Physiologist
Sterility in Rio de Janeiro, affirmed that “the problem of Hudson B (Australia) Reproductive endocrinologist
human reproduction is now accepted as a medical and bio- Madhwa Raj HG (USA) Endocrinologist
logical challenge demanding broad and varied investigation Nieschlag E (Germany) Reproductive endocrinologist
Orgebin-Crist M-C (USA) Epididymal physiologist
. . . and is a major public health problem” (4).
Reyes A (Mexico) Physiologist
In 1963 with world opinion changing, WHO started to Setchell BP (Australia) Physiologist
support research on a broad range of biomedical topics, Sheth AR (India) Endocrinologist
Short RV (UK) Endocrinologist
made possible by a contribution of $500,000 from the U.S. Waites GMH (UK) Physiologist
government. With the endorsement of the World Health Xue SP (China) Biochemist
Assembly, which was concerned about the effect of the
Waites. WHO and male contraception. Fertil Steril 2003.
contraceptive pill on the health of women, WHO established
a Human Reproduction Unit in 1965. From 1966 to 1971,
this unit quickly developed research projects, prepared
guidelines for clinical trials, conducted courses, and desig- TASK FORCE RESEARCH AND
nated a WHO Reference Centre on Drugs for the Treatment DEVELOPMENT: 1973–1979
of Infertility in Israel and a WHO Research and Training The first Steering Committee of the Task Force was
Centre at the Karolinska Institute in Sweden. Thus, the formed under the chairmanship of C. Alvin Paulsen (Seat-
groundwork was established for the formation of HRP in tle), and the first committees comprised 18 scientists from 13
1972. countries (Table 1). Three lines of research were identified:
the mechanisms of action of drugs, e.g., orally active anti-
HRP established two components: Research and Devel-
androgen cyproterone acetate and ␣-chlorohydrin; epididy-
opment, receiving two thirds of the budget, and Resources
mal function; and the collection of human epididymal ma-
for Research for institution-strengthening in developing
terial. Thus, the early objectives included a major effort to
countries. Both were supported by a Statistics and Data
better understand the epididymis and sperm maturation. In
Processing Unit, a unique asset for a WHO activity. The
the committee’s first year, 16 investigators from 10 countries
research programs were based on Task Forces for “mission-
were involved, and the budget allocation was $300,000.
oriented collaborative research on new fertility regulating
methods.” One, established in 1972, was called “Methods for By 1973, the research had been enlarged to include two
the Regulation (in the Male) of the Fertilizing Ability of broad aims: the development of methods that inhibit sper-
Sperm.” Its objectives did not include male infertility, im- matogenesis, including studies on inhibin of testicular origin,
munology, or sperm migration in the female tract, which and of methods that interfere with sperm maturation. The
were to be covered by other Task Forces (5). By 1973, the number of scientists involved had since doubled, and the
name “Task Force on Methods for the Regulation of Male budget had increased to $408,500.
Fertility” was adopted and became known informally as the
Multicenter Clinical Trials
“Male Task Force.”
The first multicenter clinical trials were planned and
Through the involvement of some 70 clinical and scien- cofunded with the Population Council and the Ford Founda-
tific colleagues from 13 developed and 12 developing coun- tion. Seven androgen–progestogen combinations were stud-
try institutions, who formed the Steering Committees be- ied at seven centers in six countries, and trials of cyproterone
tween 1972 and 2000, and of more than 300 principal acetate were conducted at four centers in four countries. The
investigators, the Male Task Force has published more than most effective combination was depomedroxyprogesterone
900 research papers and review articles in scientific and acetate and T enanthate or T-cypionate, given by injection.
health policy journals. These articles provide lasting testi- These regimens induced azoospermia in about half the men
mony to the contributions of WHO to male fertility regula- and rendered most of the remainder oligozoospermic (6).
tion for nearly 30 years. Clinical trials of cyproterone acetate also demonstrated con-

2 Waites WHO and male contraception Vol. 80, No. 1, July 2003
sistent reductions of sperm counts associated with sharp
decreases in plasma T levels because of the progestagenic
effect of cyproterone acetate.
These clinical trials set the stage for the future. The Task
Force wanted to develop animal models to test human sperm
function using the mouse or hamster zona-free oocyte pen-
etration test, but ethical concerns led the WHO Global Ad-
visory Committee on Medical Research to prohibit the use of
such techniques in WHO studies.
The World Health Organization can bring together exper-
tise from around the world to discuss issues of public health
concern. Such a consultation was convened in 1978, to
explore whether steroids given to men as a method of fer-
tility regulation could have adverse effects on prostate func-
tion. It concluded that while the causes of benign prostatic
hypertrophy and prostate cancer were largely unknown, an-
drogens may play a permissive or regulatory role once either
process had been established. It was suggested that the upper
age limit for men in clinical trials involving androgens
should be 45 years.
Basic Science Research
To determine whether suppression of FSH alone might
suppress spermatogenesis, a wide-ranging program was con-
ducted into the isolation and mechanism of action of inhibin,
a Sertoli-cell peptide believed to provide negative feedback
control of FSH. At this time, the scientific community was
taking little interest in inhibin and its significance for testic-
ular function (7). Conflicting results in nonhuman primates
based on immunization procedures suggested that FSH acts
in a permissive, rather than an essential, role in the mainte-
nance of spermatogenesis (8).
Another basic research program was supported to estab-
lish whether interference with an androgen-binding protein
secreted by rat Sertoli cells and carried in the testicular fluid
to the epididymis, might disrupt sperm maturation. However,
it could not be demonstrated that the human testis produces
androgen-binding protein, nor that this substance differs
immunologically and functionally from serum T binding
globulin.
Post-Testicular Action
Owing to the belief that a post-testicular agent would
have a more rapid antifertility effect and a correspondingly
more rapid recovery than would agents that act on spermat-
ogenesis, a dual approach was pursued. Physiologic studies
on the environment in the epididymis and on the motility of
human sperm in the proximal region of the epididymis were
conducted to confirm that passage through this region was
necessary for the maturation of sperm motility. In parallel,
the studies on ␣-chlorohydrin, which was shown to interfere
with sperm maturation in the epididymis of several species
(including nonhuman primates), had to be terminated in
1976 because of toxicity at higher doses.
FERTILITY & STERILITY威
TABLE 2
Task Force activities, 1973–1979.
The first multicenter trials
7 androgen–progestogen combinations in 7 centers in 6 countries
Cyproterone acetate at 3 dose levels in 4 centers in 4 countries
WHO–NICHD–IOCD steroid synthesis program
Production and screening of novel long-acting testosterone esters
Inhibin of testicular origin
Research was terminated in 1978 but led to an inhibin standard
Androgen-binding protein
Research was terminated in 1978
Post-testicular approach
␣-Chlorohydrin and the 6-chloro-6-deoxy sugars demonstrated the
feasibility of the approach, but both were found to be toxic
WHO consultation, 1978
On steroids and prostate function
Protocol for a contraceptive efficacy trial
Received in-house approval with depomedroxyprogesterone ⫹ T
enanthate as the drugs
Note: IOCD ⫽ International Organization for Chemical Sciences in Devel-
opment; NICHD ⫽ National Institute of Child Health and Human Devel-
opment; WHO ⫽ World Health Organization.
Waites. WHO and male contraception. Fertil Steril 2003.
At this time, chlorine-substituted sugars (6-chloro-6-de-
oxy sugars) given by mouth were shown to render male rats
reversibly infertile within 2 to 5 days, an effect confirmed in
marmoset monkeys (9). These promising compounds also
had to be abandoned because of neurotoxicity at higher than
contraceptive doses. Nevertheless, these studies convinc-
ingly demonstrated that the epididymal, post-testicular ap-
proach to male contraception was feasible.
Decision To Suspend the Task Force
From 1973 to 1979, apart from gossypol and vasectomy,
the Task Force had identified all the potential leads in male
fertility regulation (Table 2). It had also initiated high-risk
basic research programs perceived to be relevant to its mis-
sion-oriented mandate. However, the most important ele-
ment was the establishment of multicenter clinical trials,
which were not only identifying potential antifertility drugs
but also underpinning the Special Programme’s policy of
strengthening institutions in developing countries.
Nonetheless, the activities of the Task Force were sus-
pended in 1979. The reasons given by an Advisory Group
were the perceived need for large-scale investment in basic
science; the relatively few investigators in this area, although
the number involved in the Task Force’s activities had in-
creased by more than fourfold; the perceived lack of research
establishments believed to be capable of working in this
area; and reservations about the extent to which men would
use a male method. Budgetary constraints at the time were
probably also a factor in the decision. Even so, the Pro-
gramme was requested to monitor the field for developments
justifying “the reinitiation of mission-oriented research” by
the Task Force.
3
 ACTIVITIES DURING SUSPENSION OF
THE TASK FORCE: 1980 –1982
Several important activities continued. Testosterone ana-
logues from a steroid synthesis program continued to be
screened for their long-acting properties. The WHO Plants
Task Force found that 15 of 170 plants in their database were
effective in causing sperm suppression in rats, but only at
high doses, and some were linked to embryotoxicity. The
first edition of the WHO Laboratory Manual for the Exam-
ination of Human Semen and Sperm-Cervical Mucus Inter-
action was published in 1980; now in its fourth edition, this
manual has been translated into several languages (10).
To increase knowledge and technical awareness in an-
drology, a series of Andrology Training Workshops were
initiated, the first of which took place in Singapore in 1980.
This workshop was attended by participants from 10 coun-
tries in southeast Asia and the western Pacific region, and it
established the pattern for future workshops (11).
A significant development came in 1979 with the request
to the Special Programme by the People’s Republic of China
for collaborations in basic and clinical science and in epide-
miologic research in fertility control. Linked to major new
funding for family planning research in China from the
United Nations Fund for Population Activities (UNFPA),
this collaboration provided immediate opportunities for re-
search on gossypol and on the safety and efficacy of existing
and new vasectomy procedures. Moreover, these develop-
ments heralded the start of a process of institution-strength-
ening in China that was to allay concerns about the perceived
lack of trained investigators and of well-founded centers in
male fertility regulation.
The Family Planning Research Institute in the province of
Sichuan was identified as one center to be strengthened
under the China-WHO-UNFPA collaboration. This coin-
cided with concerns about the long-term safety of vasectomy
arising from animal studies suggesting possible adverse car-
diovascular effects. In Sichuan alone, some 10 million men
had accepted vasectomy as the family’s birth control
method, and some men had been vasectomized for more than
30 years.
After a consultation in 1981 entitled “Sequelae of vasec-
tomy,” a team of consultants and the Chinese investigators at
the Sichuan Family Planning Research Institute prepared a
protocol for an epidemiologic study on the possible cardio-
vascular sequelae of vasectomy. This became a major com-
mitment for the Task Force over the next 3 years. It preceded
the creation of a new Task Force on the Safety and Efficacy
of Fertility Regulating Methods, which was formed to eval-
uate methods approved for marketing, on the basis of epi-
demiologic and biostatistical procedures (12).
4 Waites WHO and male contraception
REINSTATEMENT OF THE TASK
FORCE: 1982
Disbanding the Task Force had provoked widespread
adverse comment among the scientific community and from
some member states. The Programme itself had not made it
clear that substantial activities would be continuing. A meet-
ing of experts representing the recently formed International
Society of Andrology proposed that studies should be reini-
tiated in selected areas, and these proposals were endorsed
by a refreshed Advisory Group. The resumption of Task
Force research in 1982 was approved to include, as new
features, studies on vasectomy and on gossypol. It was also
agreed that the research could now include IVF techniques,
such as the zona-free hamster oocyte sperm penetration test
(13), later evaluated in a Task Force consultation (14).
The damage caused by the cessation of the Task Force’s
research for almost 3 years at a time when it was at the
forefront of progress in the field is hard to estimate. For
example, in 1979, clinical protocols to assess the down-
regulatory effect of GnRH agonists on spermatogenesis and
to conduct contraceptive efficacy trials had been drafted by
the Steering Committee. Studies on GnRH analogues had to
be reinitiated 3 years later, and contraceptive efficacy studies
were delayed until 1985. The Scientific and Technical Ad-
visory Group, which succeeded the earlier Advisory Group,
stated: “Although the prospects of bringing into widespread
clinical use a new male chemical contraceptive in the near
future could not be regarded as encouraging, nevertheless it
was to be hoped that never again would the Programme
abandon all research in this area. The Group was gratified to
see . . . that WHO was now the most active organization in
male contraceptive development.”
TASK FORCE RESEARCH AND
DEVELOPMENT: 1982–1987
Although vasectomy, vasovasostomy, and gossypol occu-
pied much research effort from 1982 to 1987, the emphasis
shifted toward hormonal methods and assessment of the
functional capacity of residual sperm after drug suppression.
Studies in the 1960s and 1970s had demonstrated that an
androgen, alone or in combination with a progestogen, could
suppress spermatogenesis to azoospermia in about half of the
men treated. Apart from one study in India (15) and others in
Latin America (16), the issue of residual sperm concentra-
tion was studied mainly in western centers. The suppression
was shown to be reversible, and no serious adverse effects
were observed. However, a meeting conducted by the U.S.
National Institutes of Health was undecided about whether
azoospermia or oligozoospermia would be required for ad-
equate contraceptive efficacy (17). This laid the groundwork
for the landmark efficacy studies (Tables 3 and 4).
It was recognized that the short-term action of available
androgens was unsuitable for antifertility applications and
Vol. 80, No. 1, July 2003

TABLE 3
Task Force activities, 1982–1987.
Vasectomy
Chengdu epidemiologic study; novel vas occlusions, safety and
reversibility
Gossypol
Clinical reversibility
Analogues and screening by Contraceptive Development Branch
Formal rat and monkey toxicology
All research terminated in 1986
Drugs with postmeiotic or post-testicular action
The first HRP basic science program was established in 1987 to
stimulate research in this area
The hormonal program
Long-acting T esters; patent preparation and preliminary toxicology of
T buciclate
Contraceptive efficacy study initiated, based on the earlier protocol but
using T enanthate alone and exploring azoospermia first
GnRH analogues: largely a “watching brief” because of incomplete
suppression (agonists), histamine release (antagonists), and expense
Complete reversibility after 3 years of suppression to azoospermia by
pump infusion of a GnRH agonist to bonnet monkeys
Functional capacity of residual sperm
During drug-induced (depomedroxyprogesterone ⫹ T enanthate, T
enanthate alone) suppression using in vitro techniques
Waites. WHO and male contraception. Fertil Steril 2003.
that there was a need for longer-acting T esters. Fifty of these
derivatives, synthesized by chemists of the International
Organization for Chemical Sciences in Development
(IOCD) in a WHO Programme (18), were screened by the
Contraceptive Development Branch of the National Institute
for Child Health and Human Development (NICHD) for a
more prolonged action than that of T enanthate. This activity
demonstrates the strength to be derived from cooperation
between agencies with matching expertise.
Several new products emerged that it was thought would
be welcomed by the pharmaceutical industry, especially for
the benefits they would provide for the treatment of hypo-
gonadism. The anticipated industry collaboration did not
occur. The patent situation for these novel compounds was
perceived to be insecure, and they were probably seen as
competitive with existing marketed preparations.
Vasectomy
Cardiovascular status
Concerns about possible cardiovascular effects of vasec-
tomy led to epidemiologic studies on vasectomized men in
the United Kingdom and the United States (19). It was
clearly relevant to have studies in men of different dietary
and cardiovascular status. The historical cohort study con-
ducted by the Institute in Chengdu, Sichuan, China, uniquely
illustrates the benefits of the WHO approach to institutional
strengthening.
FERTILITY & STERILITY威
The cohort study brought training opportunities to Chi-
nese colleagues and data management software and other
equipment to the Institute. The Chengdu center became
experienced in the conduct of large field studies and in the
complex analysis of the resulting data. Five members of the
Chinese team were brought to Geneva to take part in the data
analysis and to help draft the report. A pilot study on groups
of 700 men showed that the nonvasectomized controls were
less healthy. Moreover, clinical examinations of nearly 4,600
vasectomized farmers from eight rural communes, some of
whom had been vasectomized for up to 25 years, revealed
that they were marginally healthier for a wide range of health
indicators, including signs of cardiovascular disease, than
the 4,300 controls (20).
Prostate
Because vasectomy altered the steroid composition of sem-
inal plasma, and animal studies had suggested that steroids in
the fluids of the excretory ducts may provide local support to
the accessory glands, it seemed possible that vasectomy could
alter prostate size and function. A letter to urologic experts
failed to elicit evidence of a relationship between vasectomy
and benign prostatic hypertrophy. A Danish group reported that
the periurethral portion of the prostate was smaller 1 year after
vasectomy. However, a Task Force–funded retrospective study
concluded that vasectomy of 8 years’ duration had no long-term
effects on prostate size (21). Although concerns about possi-
ble health consequences of vasectomy have been raised from
time to time, WHO–National Institutes of Health consulta-
tions have consistently found no evidence to support these
concerns or to justify removing this method from family
planning programs (22, 23).
Reversibility
The Special Programme’s mandate requires that family
planning methods be reversible. Although vasectomy is not
offered as a reversible procedure, and relatively few men
request vasovasostomy (24), reversibility is important for the
overall acceptability of the method. The Task Force there-
fore conducted studies in the Republic of Korea, and later in
China, suggesting that the degree of the immune response to
the vasectomy influenced the success of the reversal in terms
of pregnancy outcome.
In 1984, several new Chinese techniques of vas occlusion
were reported to the Steering Committee, and an immunologist
and a surgeon visited Chinese centers to evaluate the different
procedures for their efficacy and potential for successful rever-
sal. This paved the way for a major 10-center trial in China,
supported by the Task Force in collaboration with the State
Family Planning Commission, to compare three methods of vas
occlusion and their reversibility in small cohorts of volunteers
(25). This trial has been influential in guiding Public Health
policy in China as to the most acceptable method of vas
occlusion, and WHO has acted to publicize the “no-scalpel”
vasectomy technique throughout the world. The trial again
5
illustrated the need for training of both clinical investigators
and technicians in semen analysis and for strengthening the
capacity of the monitoring center to collect and analyze the
data.
Gossypol
After the Chinese clinical trials in the 1970s (26), gossy-
pol was proposed as a drug for male contraceptive use.
Small-scale clinical studies started in Austria and Brazil. The
World Health Organization invited Chinese scientists to a
meeting of a chemical synthesis program in 1980 in which
criteria of purity, the need for standard preparations, and the
strategy for the synthesis of new gossypol analogues were
established. However, WHO site-visiting teams to China
raised concerns about the safety of gossypol and in 1981, Dr.
Kessler decided that WHO could not be associated with new
clinical studies without more complete evidence of safety.
This decision took place while the Task Force was in abey-
ance. On its reemergence, the Steering Committee decided
its gossypol strategy, which was to absorb about half its
budget during the next 4 years.
Gossypol Synthesis Program
This collaborative program with the NICHD aimed to
produce analogues of gossypol in the hope of finding a less
toxic agent than gossypol itself. To do this, IOCD identified
13 centers in four developing countries, three developed
countries, and four countries designated at that time as “in
transition” (Yugoslavia, the Soviet Union, Bulgaria, and
Poland). Each center was allotted precise modifications of
gossypol, of which 1 to 5 g of more than 98% pure com-
pounds were to be produced. By 1985, 78 analogues had
been produced, of which 37, after quality control testing by
the London analytical center, were tested by the NICHD
Contraceptive Development Branch in a hamster assay.
None was more active than gossypol itself.
Because unreliable information was appearing in the lit-
erature owing to the variable purity of the gossypol being
used, a pure standard of gossypol acetic acid was distributed
to the scientific community. This was prepared by NICHD
and its purity and stability established by four centers (Bei-
jing, Chicago, London, and the NICHD). A large batch of
gossypol acetic acid under “good manufacturing practice”
was then commissioned for evaluation of the antifertility
activity in the rat, for toxicity studies in laboratories accred-
ited to international drug regulatory standards, and to de-
velop a radioimmunoassay. Since the naturally occurring
(⫹)-gossypol was inactive, it was also decided to isolate and
test the (⫺)-gossypol enantiomer.
Chemists at the Institute of Materia Medica, Beijing,
produced 3 kg of pure gossypol acetic acid, of which 1 kg
became the standard dispensed into vials by Schering AG,
Berlin, free of charge. The remainder, after recrystallization
under GMP, became the source material for all future stud-
ies. The Central Drug Research Institute, Lucknow, also
6 Waites WHO and male contraception
prepared more than 1 kg of gossypol acetic acid, which was
used in the synthesis program. Meanwhile, racemic gossypol
was resolved into its constituent isomers (enantiomers) by
the London and Beijing chemists, providing (⫺)-gossypol
for biological testing. This confirmed that (⫺)-gossypol had
a twofold increase in activity compared to gossypol acetic
acid. Thus, by 1984, through the dedicated effort of the chem-
ists, the scene was set to establish the safety of gossypol.
Toxicology
Waites et al. (27) described the events leading to the
abandonment of gossypol as a potential drug. Toxicity stud-
ies revealed that the rat was relatively resistant to the effects
of gossypol but that gossypol was lethal in cynomologus
monkeys at a daily dose of 25 mg/kg of body weight, which
was only 2.5 times the antifertility dose in the same species.
The pure (⫺)-gossypol was toxic to cynomologus monkeys
at 4 mg/kg daily, and even at the low daily dose of 1.5
mg/kg, there were clinical signs involving the gastrointesti-
nal tract and reduced liver weight. Together with reports of
gossypol-associated hypokalemia in the Chinese clinical tri-
als, the WHO-HRP Toxicology Group concluded that both
forms of gossypol were too toxic to be developed for human
contraception.
Clinical investigators in Beijing and Nanjing found that
39% of men treated with gossypol failed to recover to
pretreatment baseline sperm concentrations after nearly 2
years of follow-up, and 22% of all men remained sterile.
The failure to recover was strongly associated with longer
time of treatment, greater total dose of gossypol, smaller
testis volume, elevated serum FSH concentrations, and, to
a lesser extent, greater body weight. A similar incidence
of sterility was observed in the Brazilian study. The
WHO-HRP Scientific and Ethical Review Group recom-
mended that no further studies with gossypol be under-
taken. Soon after, clinical studies in China and a study on
langur monkeys in India both showed that gossypol treat-
ment directly induced hypokalemia, possibly via impair-
ment of kidney function. In 1986, Chinese and interna-
tional scientists decided to discontinue work on gossypol
as a potential contraceptive drug (28).
Conclusion
Some agencies and investigators continued to promote
research on gossypol in the context of a drug discovered by
a developing country requiring less stringent levels of ap-
praisal. Clinical studies were continued in Brazil. It was
argued that irreversibility was of little consequence for men
requesting contraception, and parallels with vasectomy were
suggested. Some investigators in China also felt that WHO
had abandoned the quest for safe gossypol analogues too
early. Nevertheless, once testicular toxicity had been re-
vealed, there was no alternative for WHO, given its mandate
to develop only safe, reversible methods by means of appro-
priate animal toxicology and phased clinical studies.
Vol. 80, No. 1, July 2003
 TABLE 4

Task Force activities, 1988 –1996.

Contraceptive efficacy studies (1990 and 1996)

Established that overall pregnancy rate in men with sperm concentrations suppressed to 0–3.0 million sperm/mL was 1.4 per 100 person-years
Ethnic differences in suppression revealed
Long-acting testosterone esters
T-buciclate tested in phase I studies in hypogonadal and normal men with excellent results; halted because of toxicology and formulation issues
Injectable T undecanoate developed in monkey and clinical studies and introduced in China
Progestogen–androgen (depomedroxyprogesterone ⫹ T enanthate or 19NT)
Effective in sperm suppression in Indonesian men (5-center trial) (38)
Second-generation levonorgestrel (butanoate and T buciclate) steroids yielded promising results in primate studies
Vas occlusion
Efficacy of silicone plugs examined
A 10-center phase II study in China compared the efficacy and reversibility of 3 vas occlusion methods
Workshops in vas occlusion techniques conducted in Beijing and Surabaya
Vasectomy and the risk of cancer
Consultations concluded that any causal relationship between vasectomy and prostate or testicular cancer was unlikely
Antifertility drugs derived from Tripterygium wilfordii
Selected active compounds identified and triptolide explored for epididymal site of action
Basic science program
Some 40 projects supported to identify new targets in the postmeiotic phase of sperm maturation

Waites. WHO and male contraception. Fertil Steril 2003.

TASK FORCE RESEARCH AND
DEVELOPMENT: 1987–1996
Because a belief remained that plants might provide new
antifertility drugs, a Task Force on Plants for Fertility Reg-
ulation was established. Moreover, the WHO Tropical Dis-
ease Research Programme was collaborating with Chinese
scientists in the development of artemesinin of plant origin,
an effective antimalarial drug.
Tripterygium wilfordii
In 1986, root extracts of Tripterygium wilfordii, a tradi-
tional herbal medicine for treatment of psoriasis and other
dermatologic conditions, were shown to have a reversible
antifertility action in male rats in a Task Force–supported
study (Table 4). The historical and biomedical background to
this observation was published (29), and a collaborative
agreement with the Jiangsu Family Planning Research Insti-
tute, Nanjing, was established. The aims were to isolate,
identify, and test purified fractions for biological activity; to
conduct preliminary toxicology and pharmacology profiles;
and eventually to conduct clinical studies. This international
coalition of laboratories, coordinated from Geneva (Fig. 1)
(30), again demonstrated the commitment of WHO to col-
laborative research in the interests of drug development in
developing countries.
The chemical isolation work started in London, with the
assistance of a WHO research trainee from Nanjing, and in
Bangkok, using root extract provided by the Jiangsu Provin-
cial Government. Meanwhile, the Task Force supported a
follow-up study in Nanjing on the recovery of spermatogen-
esis in patients treated for mild psoriasis, to be sure of the
reversibility of its action. Triptolide and other triterpenes
extracted from the plant were found to have a post-testicular
antifertility effect (31), but recently a testicular toxic effect
has been revealed. Thus, the options for drug development
are not promising.
Drugs With Postmeiotic or Post-Testicular
Action
Drugs with postmeiotic or post-testicular action would
not disturb spermatogenesis, libido, or any other hormonally
related feature. Their effects would be rapid both in onset
and in the return of normal sperm on withdrawal of the drug.
The Task Force supported studies in Hong Kong to ex-
plore such drugs as sulfasalazine and its analogues for their
transport and action on the fluid environment of the epidid-
ymis. Several analogues had an antifertility action that may
be mediated through effects on maturing spermatozoa after
specific accumulation in the epididymis. New drugs devel-
oped by the IOCD were also screened by this laboratory.
With the acknowledgment that drugs with an action on
sperm maturation had arisen by serendipity (e.g., sulfasala-
zine), a symposium was held from Mexico in which an open
program of basic research emerged (32). The focus was on
novel means of interfering with unique features of spermio-
genesis and sperm maturation.
The Basic Science Research Program
In 1987, projects were solicited. The budget was re-
stricted to $10,000 per project, and from an initial response
of 42 summary applications, 14 full applications were in-
vited for further review. Three main areas of research focus
emerged: spermiogenesis, the molecular biology of the
sperm membrane and its role in sperm– egg recognition, and

FERTILITY & STERILITY威 7

 FIGURE 1
The structure of the World Health Organization collaborative research program on Tripterygium wilfordii (30).
Waites. WHO and male contraception. Fertil Steril 2003.
sperm surface ion channels and the development of sperm
motility. Expanded applications were requested after 1 year
if the results were relevant to the mission-oriented approach.
Laboratories in developing and developed countries re-
sponded. In the former, the budget provided all or most of
the requirements, whereas for the developed countries, the
budget enabled focused studies within larger programs with
existing techniques.
The program was deemed a success, and it was unique at
that time in that the area of research needing attention was
first defined. This pattern was adopted by other Task Forces
and later attracted cofunding from the Rockefeller Founda-
tion. Later still, the concept was continued in the form of a
Rockefeller Foundation-Ernst Schering Research Founda-
tion–funded activity, called “Application of Molecular Phar-
macology for Post-testicular Activity.”
The Search for a Hormonal Method
The strategy for hormonal methods was based on the
conduct of multicenter clinical studies, the development of
long-acting androgens, the exploration of combination pro-
gestogen–androgen regimes, and the promise offered by
GnRH analogues (33). The prevailing view was that only
long-acting versions of GnRH agonists would be sufficiently
8 Waites WHO and male contraception
effective in sperm suppression, whereas GnRH antagonists
might be of interest when low-cost analogues without hista-
mine release at the injection site were available. Concerns
about reversibility after long-term suppression, which were
raised by observations in older men treated with GnRH
analogues for prostate cancer, led to a study in Bangalore in
which bonnet monkeys were suppressed to azoospermia for
3 years by pump infusion of a GnRH agonist with T enan-
thate by injection. Full recovery to fertility occurred on
cessation of the treatment. Thus, issues of safety—for ex-
ample, about steroidal drugs inducing changes in lipid me-
tabolism, reversibility after long-term suppression of sper-
matogenesis and, in the case of GnRH analogues, their cost
for developing countries—were shaping the Task Force’s
strategy.
It had long been known that T, in one formulation or
another, could be an antifertility drug by its suppression of
the secretion of gonadotropins while simultaneously provid-
ing support for androgen-dependent functions. The wide-
spread clinical use of androgens for the treatment of hypogo-
nadal men had suggested that their use for suppression of
sperm production in normal men would be safe. Knowledge
was insufficient of likely long-term effects, although evi-
Vol. 80, No. 1, July 2003
dence was accumulating that administration of T to maintain
circulating levels in the normal range was safe. Similar
uncertainties had existed at the equivalent stage in the de-
velopment of female hormonal drugs. If other agents were
used to suppress gonadotropin secretion, supplementary an-
drogen would be needed to maintain systemic T levels in the
normal range. Thus, it was evident that slow-release prepa-
rations were needed to increase the interval between succes-
sive administrations.
Esters of Testosterone
The Task Force had been identifying long-acting T esters
arising from the WHO–NICHD–IOCD program to synthe-
size novel steroids for antifertility regimens (18). From an-
imal assays, two were judged to be particularly promising:
levonorgestrel butanoate for female use and T buciclate
(testosterone trans-4-n-butyl cyclohexylcarboxylate) as a
long-acting androgen for men. T buciclate was selected
because in two centers (Münster and New Delhi), a single
injection of a milled aqueous suspension to castrated mon-
keys recovered and maintained serum T levels in the phys-
iologic range for up to 3 months, without the high initial
peak of release characteristic of T enanthate (34). Neverthe-
less, 5 major pharmaceutical companies declined to collab-
orate in the development of T buciclate, citing the relatively
small market for hypogonadal patients and the insecurity of
the patent position. This left the Task Force to develop this
promising drug itself, without the resources available to drug
companies and relying mainly on academic centers for as-
sistance.
Small-scale, phase I, dose–response studies were con-
ducted in hypogonadal patients at three centers in Europe,
China, and Indonesia, and in normal men in one center.
These demonstrated the long-term effects and justified the
selection of T buciclate both for treatment of hypogonadal
patients and for its ability to suppress spermatogenesis in
healthy men (35). In anticipation that T buciclate would be
the long-acting androgen of choice, a U.S. patent application
was filed by Dr. G. Bialy and Contraceptive Development
Branch colleagues.
Before agreeing to further phase I or II studies, the WHO
Toxicology Panel required a formal toxicology profile using
standard assays and answers to two questions: the fate of the
side chain, presumed to be metabolized by the liver, and
whether T buciclate was a true prodrug. These requirements
proved costly in time and money. Such stringent toxicologic
evaluation had not been required for levonorgestrel butano-
ate, which has a similar side chain (cyclobutyl ester), before
earlier approval for phase II and III studies in women, an
indication of the ever-increasing constraints of drug devel-
opment. During the delays in T buciclate development,
which were exacerbated by formulation problems, an inject-
able form of T undecanoate in tea seed oil was produced in
China and found to have more favorable pharmacokinetics
FERTILITY & STERILITY威
than T enanthate (36). Subsequently, T undecanoate was
formulated in castor oil and shown to have similarly favor-
able pharmacokinetics in nonhuman primates and in clinical
studies (34).
Contraceptive Efficacy Studies: Genesis
The protocol for a contraceptive efficacy study, approved
“in house” in 1979 after several years of persuasive effort,
was resurrected. The protocol was for a study with de-
pomedroxyprogesterone acetate and T enanthate but was
shelved when the Task Force was disbanded. The aims were
to explore first the contraceptive efficacy of men who
achieved azoospermia and then, in a second study, the effi-
cacy of oligozoospermia. The protocol for the azoospermia
study was redrafted with T enanthate alone instead of the
depomedroxyprogesterone acetate–T enanthate combination.
This change was made because a single drug is easier to
administer, substantial toxicology data on T enanthate had
demonstrated its safety, and long suppression of the hypo-
thalamic–pituitary axis by depomedroxyprogesterone acetate
would be avoided. In addition, two Task Force–supported
studies suggested that depomedroxyprogesterone acetate
may be responsible for a decrease in plasma high-density
cholesterol levels, the significance of which was unknown
but considered to be undesirable.
In the first trial, men becoming azoospermic after weekly
injections of T enanthate were to have unprotected inter-
course with their partners for 12 months. The Steering Com-
mittee decided on the recruitment targets, the entry, and
discontinuation criteria, and by mid-1986, a revised version
of the protocol had been approved by the WHO Toxicology
Panel and Review Group. This protocol was then sent to
investigators through the usual WHO channels, (i.e., the
Ministries of Health), and 10 centers in seven countries
offered to participate.
Comments from investigators were incorporated into the
protocol. The original requirement for a previous pregnancy
in the partner was dropped and the recruitment target set at
240 couples. The forms designed by the HRP statistical
personnel ensured uniform standards for the centers and
provided tables to be completed throughout the study so that
individual center data on subject characteristics, semen anal-
ysis, and hormonal and biochemical measurements could be
monitored. Strict procedures for reporting pregnancies and
arrangements for monitoring individual center performance
were established. All data were collected and analyzed by
the Statistics and Data Processing Unit of the HRP. Schering
AG provided the T enanthate free of charge for this study
and the second efficacy study, as did ER Squibb (later
Bio-Technology General Corp.) for the two U.S. centers;
both U.S. centers were fully funded by the Contraceptive
Research and Development Program (CONRAD).
9
Contraceptive Efficacy Studies: Conduct
By mid-1988, the centers had started recruitment, al-
though the rate varied. In addition, three studies offered
reassuring evidence that the function of residual sperm pro-
duced by men suppressed with T enanthate or de-
pomedroxyprogesterone acetate plus T enanthate was de-
pressed or abolished. By late 1989, the target exposure of 91
patient-years had been reached, and the efficacy part of the
study was stopped in all centers in April 1990.
Great variation in the degree of suppression to azoosper-
mia was noted. In the Chinese centers, 91% of men became
azoospermic, whereas in the European centers, only 60% of
men became azoospermic, a remarkable difference by eth-
nicity. The mean minimum concentration among the 30% of
men in whom azoospermia was not achieved was 3.0 million
sperm/mL. The investigators (37) reported that there had
been only one pregnancy, yielding a Pearl index of 0.8 per
100 person-years for azoospermic men. Interest and specu-
lation were widespread about the next multicenter trial,
which would be done to determine the minimum suppression
level needed to ensure safe and acceptable contraceptive
efficacy in oligozoospermic men.
Meanwhile, looking ahead to when hormonal methods
would be introduced into family planning programs in
developing countries, it was agreed with Indonesian Author-
ities that a five-center study should be undertaken in Indo-
nesian men on the sperm-suppressing effect of depomedroxy-
progesterone acetate combined with either T enanthate or 19
nortestosterone. This required the creation of trial guidelines
and visits by temporary advisers and the statistical team to
advise the clinical investigators and train local data analysis
personnel. The high rates of azoospermia induced by andro-
gen–progestogen treatment in Indonesian men (38) con-
firmed that Asian men are more susceptible than non-Asian
men and provided the groundwork for the studies currently
being conducted in Indonesia.
In the second efficacy study, organized at an investiga-
tors’ meeting in Beijing in July 1990, men who were sup-
pressed to azoospermia or to severe oligozoospermia on the
same drug regimen were to have unprotected intercourse for
12 months. The threshold sperm concentration chosen for
this efficacy trial was less than 5 million/mL. The study was
conducted in 399 couples at 15 centers in nine countries
from 1990 to 1994. The incidence of pregnancies first indi-
cated that the oligozoospermic threshold for inclusion in the
efficacy phase was too high. The Steering Committee then
lowered the threshold to less than 3 million sperm/mL after
analysis of the pregnancy rates stratified by sperm concen-
tration.
Altogether, 98% of all men had suppression to less than 3
million sperm/mL. No pregnancies occurred when the men
were azoospermic and only four in 49.5 person-years with
sperm concentrations 0.1 to 3.0 million sperm/mL. The
10 Waites WHO and male contraception
pregnancy rate was 8.1 per 100 person-years. Pregnancy
rates were strongly related to sperm concentrations during
the efficacy phase (Fig. 2) (39). The overall pregnancy rate
attributable to all men with a sperm concentration of 0 to 3.0
million sperm/mL was 1.4 per 100 person-years, which was
similar to first-year failure rates of modern, reversible female
methods. No pregnancies occurred in the Asian couples, who
contributed only 15% of those men who failed to reach
azoospermia (39, 40). Most men recovered to “normal”
levels (ⱖ20 million sperm/mL, by WHO criteria) by 3 to 4
months and to their baseline sperm concentrations at a me-
dian of 6 to 7 months after cessation of treatment. There
were no differences in the recovery times of men who
became consistently, never, or intermittently azoospermic.
Some couples planned pregnancies after completion of the
studies, and all term pregnancies resulted in healthy infants.
Several important features were included in the protocols:
for example, the partner’s age at entry was increased from 35
to 38 years; couples kept a diary of menstrual bleeding and
sexual activity; rigorous criteria were established for entry
into the efficacy phase (three consecutive specimens with
sperm concentrations under the predefined thresholds); and
if escape from suppression occurred during efficacy, sperm
concentrations were assessed at 2-week rather than monthly
intervals (41). Thus, the protocols for the safe conduct of
contraceptive efficacy studies represent one of the more
durable achievements of the WHO Task Force.
Questionnaires were designed to explore the acceptability
of the so-called “male method,” including behavioral as-
pects, and focus group discussions were conducted. In one
center, 61% of the participants were motivated by problems
of the female partner, including 35% who had experienced a
contraceptive failure, or by the desire to share responsibility.
Around 80% of men and their partners wanted to continue
with the male method regimen (42). Several reports were
published that examined factors involved in the different
rates of suppression to azoospermia and oligozoospermia
among the study populations (41, 43) and the metabolic
effects of T enanthate and the possible implications for
long-term safety (44). While “conclusions regarding hor-
monal effects on human behavior have to be drawn with
great care” (45), the low incidence of psychological reac-
tions was consistent with their absence in a placebo-con-
trolled study of healthy men given injections of T enanthate
(46) and with later studies using a range of psychometric
tools. The fact that 83% of the couples entering these studies
did so because of dissatisfaction with female methods, and
their willingness to continue the treatment, augers well for
the future.
RESEARCH AND DEVELOPMENT: 1997
ONWARD
The Biennial Report “Research on Reproductive Health at
WHO” (1) describes the continuing studies on hormonal
Vol. 80, No. 1, July 2003
 FIGURE 2

Relationship between sperm concentration and pregnancy rate in the World Health Organization contraceptive efficacy trial
(39). Pregnancy rates per 100 person-years in each sperm concentration stratum (inset), and according to the cumulative sperm
concentration. Bars indicate 95% confidence limits, and numbers in brackets are the number of pregnancies observed.

Waites. WHO and male contraception. Fertil Steril 2003.

methods for men. These include a phase II contraceptive
efficacy trial of monthly T undecanoate injections in China,
in which there were no pregnancies for 1 year among 290
couples and an ongoing 10-center phase III trial in China of
up to 1,000 couples for 2 years efficacy using T undecanoate
by injection. If the latter study confirms the earlier results, T
undecanoate should become the first male hormonal contra-
ceptive to achieve registration and be introduced into na-
tional family planning use (2, 3).
Other promising studies with T undecanoate combined
with depomedroxyprogesterone acetate in Indonesian men
are also described. In addition, a phase II, 10-center clinical
trial of an 8-week injectable combination of T undecanoate
and norethisterone (47) is planned. These studies should
determine whether an androgen alone or in combination with
a progestogen should be the preferred option for male con-
traception.
“Summit Meetings on Male Contraception” have been
organized annually since 1997 by Professor Nieschlag. Dur-
ing these a “Weimar Manifesto” (33) urging greater efforts
in male contraception was issued. Also, two major pharma-
ceutical companies recently announced a joint program to
develop “an effective and safe male contraceptive” and, with
WHO and other agencies, reached the consensus statement
“Recommendations for Regulatory Approval for Hormonal
Male Contraception” (48).
DISCUSSION
In hindsight, several important features influenced the
pace of research and development of male methods of fer-
tility regulation. Some are universal, whereas others relate
more to research undertaken by an international agency.
Social, Political, and Professional Climate
There were reservations about whether men would accept
hormonal suppression of sperm production. Well-controlled
studies were lacking on attitudes to male methods in differ-
ent cultures at a time when such methods were still hypo-
thetical. Anecdotal information about risks, spread through
ignorance or prejudice, adversely affected public and, occa-
sionally, agency opinion. Perhaps most crucially, investment
and research activities into male methods did not increase in
response to sustained pressures to do so from such sources as
women’s advocacy groups (49). In addition, pharmaceutical

FERTILITY & STERILITY威 11


TABLE 5
Agencies that regularly collaborate in Task Force
activities.
Contraceptive Development Branch, National Institute of Child Health
and Development
U.S. Agency for International Development
Contraceptive Research and Development Program
International Organization for Chemical Sciences in Development
Population Council
Indian Council for Medical Research
Association for Voluntary and Safe Contraception
Waites. WHO and male contraception. Fertil Steril 2003.
companies involved in the relatively small markets for treat-
ment of male reproductive diseases were reluctant to assist in
the development of drugs for sperm suppression in normal
men. For example, certain GnRH agonists in development
for the treatment of prostate dysfunction were denied for trial
as possible contraceptive regimens. The perceived profit
margins were too small and the product liability risks too
great.
Medical graduates were reluctant to enter the new field of
andrology, a clinical entity without formal recognition in
most medical curricula. Conversely, the specialty of gyne-
cology was present in every hospital and medical school.
Gynecologists and urologists exercised a stranglehold on the
treatment of male infertility and most appeared reluctant to
support the development of methods for regulation of male
fertility. Centers in Australia and Finland reported that no
couples were referred to the efficacy studies by gynecolo-
gists, even when the female partner was having difficulties
with her own contraception, whereas recruitment was brisk
after media coverage.
Funding Limitations and the Collaborating
Agencies
Overall funding for family planning research was limited.
This meant that female methods were given higher priority,
and inevitably, funding for new male methods was insuffi-
cient. From 1987 to 1992, when the Task Force was involved
in several major ventures (e.g., the multicenter contraceptive
efficacy and other clinical studies, and developing novel
androgens) and in initiating new ones (e.g., the basic science
program), it was allocated 6.8% to 10.4% of the Pro-
gramme’s research and development budget—an average
annual amount of $532,000.
Clearly, without the cofunding support of the collaborat-
ing agencies (Table 5) for several priority activities, the
momentum achieved by the Task Force could not have been
sustained. For example, the Contraceptive Development
Branch of the NICHD committed an average of $740,000
annually (7.5% of its total budget) to “male methods syn-
thesis.” Assistance without charge was given for the chem-
12 Waites WHO and male contraception
ical synthesis programs, assays of the T esters and the
gossypol analogues, and provision of research standards for
inhibin and gossypol.
While not a regular donor, the U.S. government provided
financial support indirectly through the United Nations De-
velopment Programme, the United Nations Population Fund,
and the World Bank, which had entered into cosponsorship
of the Special Programme in 1988. In addition, the U.S.
Agency for International Development, Office of Population,
through CONRAD devoted an average of 14.7% of its total
funding to “male methods” from 1987 to 1992; over this
period, the budget of CONRAD for this activity steadily
increased. To this day, CONRAD continues to provide funds
for clinical research.
Other collaborative arrangements included the making of
a film to teach the no-scalpel method of vas occlusion by Dr.
Li Shun-qiang, which was co-funded with The Association
for Voluntary and Safe Contraception (AVSC) and the Pro-
gram for Appropriate Technology in Health. The film was
awarded a prize by the Royal College of Surgeons of Lon-
don. The basic science program, once established, was co-
funded by the Rockefeller Foundation, and later, a Schering
and Rockefeller Foundation research program in post-testic-
ular contraception was established.
Impact Through Published Research
One measure of research activity is the number of inves-
tigators receiving funds. For the Male Task Force, this num-
ber was about 60 per year from 1990 to 1992. The impact of
the research was reflected in 35 to 60 publications per year
from the mid-1980s to 1992. The average cost per publica-
tion was an economic $10,000. From 1994 to 1996, the
number of investigators contracted to undertake Task Force
research decreased to around 40 per year and then to around
11 per year from 1997 to 2000. In its lifetime, the WHO Task
Force has generated over 900 publications in scientific and
health policy journals.
Uniqueness of the Task Force Approach
The World Health Organization performs a unique coor-
dinating role in the general area of global public health, and
the Male Task Force has acted in this manner for the field of
male reproductive health. It has undertaken consultations,
involved other agencies, and, where particular expertise was
needed, has co-opted advisors (e.g., in the basic science
program and for the writing of technical manuals and pro-
tocols). By meeting twice a year, once in Geneva and once
in a developing country, usually in conjunction with a local
symposium or workshop, the Steering Committee members
could provide local training and advice. In this way, the Task
Force increased the range of its activities and influence. The
latter is illustrated by the comments of a collaborating
agency representative:
. . .WHO over the last 10 years had hosted meetings with
other collaborating agencies and . . . enabled the agency
Vol. 80, No. 1, July 2003
representatives to learn what everyone is doing . . . . NIH
runs a national programme in which the interests of the
developing countries are not of primary importance . . . the
collaboration with WHO . . . is based on trust. The Task
Force is open with respect to information transfer.
However, the projects had to be judged from social as
well as scientific perspectives, especially in the context of
institution strengthening in developing countries. No other
agency was doing this on a global level. There was no
goal-oriented program for male contraception in Europe, and
the Medical Research Councils primarily supported basic
clinical research. The basic science program was seen by
external reviewers as a unique initiative in a strategic area,
differing from that of other agencies in its specific focus
(postmeiotic and post-testicular).
Another unique focus has been training for developing
countries, often through the network of WHO Collaborating
Centers selected for their training resources and research,
both clinical and basic. In addition, with the aim of stan-
dardizing methods, the WHO has published its laboratory
manual on examination of human semen and sperm– cervical
mucus interaction and guidelines for use of androgens in
men (50). The “WHO semen manual,” now the most quoted
WHO publication, has been influential in the creation of
national quality control programs that are essential for reli-
able standardization, both within and between laboratories.
Considerable effort was also put into dissemination of
information. For example, in 1990, the Task Force’s research
was discussed in symposia or by review lectures in nine
international meetings. Andrology training workshops con-
ducted in Singapore (two), China (two), Kenya, Chile, Geor-
gia (USSR), Hong Kong, Morocco, Indonesia (two), Viet-
nam, and Russia (two), and the policy of conducting Task
Force research in developing countries have raised the com-
petence in and heightened the awareness of the need for
research into male methods throughout the world (11).
Overseeing the Task Force Research
Because the Programme’s funding comes from public
sources, balance must be maintained between basic and
applied research and the projects must undergo external peer
review. The activities and progress of all the Task Forces
were overseen by the Programme’s Policy and Coordinating
Committee and the Scientific and Technical Advisory Group
to ensure such a balance and scientific quality. Also, there
may be political sensitivities to be considered. These groups
have universally supported the Task Force’s research.
Since the studies were initiated largely to establish the
proof of principle, were not geared to drug registration, and
lacked collaborative guidance from the pharmaceutical in-
dustry, the Committee needed expert advice about toxicol-
ogy and other aspects of bringing novel compounds to the
market. The in-house recommendations often lacked the
detailed guidance needed—for example, on the appropriate
FERTILITY & STERILITY威
toxicology tests for T buciclate. The critical need to study
hypogonadal men to test the pharmacokinetics of new an-
drogens also required special pleading.
Perceptions of Risks and Benefits
Initially, the long-term risks of accelerating cardiovascu-
lar or prostate disease and the benefits of giving steroids to
normal men were unknown, as were similar risks at the
equivalent stage of female contraceptive development.
Shorter-term risks were perceived to be possible adverse
effects due to the unsatisfactory pharmacokinetics of the
androgens available and possible potentiation of aggressive
male behavior; the latter factor was exacerbated by men
taking large doses of mixed steroids for body building. Yet,
in the 1996 WHO study, only 3 of 50 discontinuations for
“personal reasons” among 399 participants were for a per-
ceived increase in aggressive behavior (39), and no such
discontinuations occurred in the Chinese study (2).
Prospective epidemiologic studies have found no relation-
ship between T levels in men and coronary heart disease (51,
52). Similarly, although the mechanism of androgen action
in the prostate remains incompletely understood, the causes
of prostate cancer are multifactorial and involve history,
race, lifestyle, diet, and family. The risk for prostate cancer
is higher, for example, if a relative has the disease (53).
Nevertheless, the consequences of giving steroids to men for
part of their reproductive life must be considered, even
though the additional risk would appear to be small.
Oudshoorn (54) has commented that safety issues, includ-
ing emotional well being, libido and sexuality, were ad-
dressed from the start by the scientists involved in male
method development. Yet even the low rates of discontinu-
ations for relatively minor side effects, such as acne, weight
gain, and transient reductions in high-density lipoprotein
cholesterol level, provoked comment by some review com-
mittees. With time, the safety issues and the stringency of the
monitoring have steadily increased. As Oudshoorn (54)
points out, the possible consequences of steroid-induced
disturbances in lipid metabolism led to the formation of the
U.S. National Lipid Education Program and an impossible
“quest for zero risk.” This increase in the climate of concern,
also fueled by litigation, has substantially inhibited develop-
ment of effective new contraceptive drugs.
CONCLUSIONS
Aspects of the WHO Task Force research could not have
been accomplished in any other environment. Only WHO,
with its known integrity, could have obtained the support of
national health ministries in both developed and developing
countries or formed the coalition of partner agencies neces-
sary for the contraceptive efficacy studies to be undertaken.
Consequently, the Task Force studies can be applied to men
of different ethnicity and to culturally diverse populations
and have enabled interpretations with universal applicability.
13
In addition, WHO can bring together the expertise able to
make influential recommendations, such as those on vasec-
tomy and cancer, and can coordinate the work of several
agencies in, for example, the chemical synthesis programs.
On the other hand, WHO was not equipped or sufficiently
well funded to develop the new drugs needed without sup-
port from the pharmaceutical industry. Certainly, had the
Programme been able to devote more funding to male meth-
ods research, more could have been achieved and faster. Had
the climate of medical opinion been more positive in the
early stages and the commitment of the pharmaceutical in-
dustry stronger, and had there been fewer prejudiced voices
and greater attention to recommendations from such groups
as women’s health advocates, undoubtedly the new methods
would have been developed much earlier.
However, recognizing that “there is a tide in the affairs of
men, which, taken at the flood, leads on to fortune” (55), the
current coalition of andrologists, public sector agencies, and
the pharmaceutical industry will surely provide the methods
needed by men willing to share in the responsibilities of
family planning (56). When this happens, the WHO Task
Force and the collaborating public sector agencies should be
given full credit for their long-term contributions.
Acknowledgments: The author thanks Ebo Nieschlag (Münster, Steering
Committee Chairman, 1985–1991) for encouraging the writing of this
review and for unswerving support during its preparation; Michael Bedford
(New York), David Handelsman (Sydney) and Christina Wang (Torrance;
Steering Committee Chairperson, 1991 onward) for advice and editorial
assistance; and Tim Farley (WHO) and other colleagues from many coun-
tries for their help and friendship during his time as Manager of the Task
Force (1983–1994). The review is dedicated to Al Paulsen (Seattle), the
“godfather” of the Task Force, and is offered in memory of Doreen.
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