"Effect of Age on Male Fertility"

Seminars in Reproductive Endocrinology

Volume 9, Number 3, August 1991
Sherman J Silber, !"
DECREASING FERTILITY OF THE WIFE IN RELATION TO AGING
Studies from the Office of Health Research, Statistics and Technology of the US. e!artment of
Health ha"e made it clear that fe#er than $% of teenage girls are infertile, &ut more than '(% of
#omen in their mid)*(s are infertile.+$),- This decrease in fertility #ith age is not a ne#
!henomenon that suddenly de"elo!ed in the $./(s. Many studies in the !ast ha"e consistently
demonstrated a decrease in fertility of older cou!les.
The 0uestion that this age)related decline in a cou!le1s fertility &rings u! is to #hat e2tent it is the
conse0uence of reduced female fertility, male fertility, or &oth. The first #ell controlled study on
this issue came from France in $./'. 3t com!ared the results of artificial insemination #ith
highly fertile donor s!erm in '$.* nulli!arous #omen #ho had a4oos!ermic hus&ands.+5- 3n
order to control for the !ossi&ility that the age of the male !artner might affect the infertility of
an older cou!le, this huge series em!loyed artificial insemination #ith uniformly fertile donor
s!erm to #omen of "arious ages o"er a !rolonged !eriod of time. The cumulati"e success rate
+as #ell as the !regnancy !er cycle- for #omen '5 years of age or younger #as similar to that of
#omen o"er '5 &ut under *$ years of age. Ho#e"er, there #as a significant decrease in the
!regnancy rate for #omen *$ to *5 years of age, and a dramatic decrease for #omen o"er the age
of *5 years. Thus, the !regnancy rate !er cycle and the o"erall cumulati"e !regnancy rate clearly
#ent do#n #ith age in #omen in #hom the male factor #as constant, +i.e., only fertile donor
s!erm #ere used-.
This large French study !ro"ed the dramatic reduction in fertility of #omen as they !ass the age
of *( years, &ecoming !rogressi"ely more se"ere during their ne2t $( years. They se!arated the
influence of the age of the #oman from other "aria&les associated #ith age, such as decreased
fre0uency of se2 #ith age as #ell as increased age of the hus&and. Their study com!letely ruled
out those issues &y using artificial insemination #ith fro4en donor semen.
A second !ro&lem they dealt #ith is that in many cases #here the hus&and is "infertile" his s!erm
count is sim!ly lo#, &ut he is definitely not "sterile." An e2tremely fecund #oman may there&y
&ecome !regnant easily &y a man #ho is e2tremely infertile. Thus, in any grou! of #omen
see6ing artificial donor insemination #hose hus&ands #ere merely oligos!ermic, there #ill &e a
significant num&er of such #omen #ho are more infertile than in a random !o!ulation of
#omen, and this may not &e related to age.+7- 8y choosing only #omen #hose hus&ands #ere
a4oos!ermic, the French authors com!letely remo"ed that &ias. Thus, it #as clear that female
fertility declines dramatically #ith age and it &ecomes most !ronounced and o&ser"a&le !ast the
age of *5 years. Further e"idence to this !oint comes from the e2tremely lo# !regnancy rates in
#omen ,( years of age or older undergoing in "itro fertili4ation. 9
The ne2t most serious 0uestion +#hich has no# &een settled- related to decrease in female
fertility #ith age is #hether the !ro&lem is caused &y the age of the o"aries +and in that res!ect
the age of the oocyte- or if it is related in some #ay to the actual age of the #oman. 3n "itro
fertili4ation +3:F- and gamete intrafallo!ian transfer +;3FT- studies using eggs donated from
younger #omen to !ostmeno!ausal #omen +often as much as '( years older- ha"e clarified this
issue incontro"erti&ly. / 3t has &een #ell esta&lished that !regnancy rates #ith ;3FT and 3:F are
much higher in younger #omen in their '(s than older #omen in their late *(s or early ,(s.
Ho#e"er, #hen em&ryos o&tained from the eggs of younger #omen are !laced into older
#omen, often in their late ,(s or early 5(s, the !regnancy rate is <ust as high as that o&tained
#ith 3:F or ;3FT in e2tremely young #omen.
3n fact, one dramatic surrogate case from South Africa in"ol"ed the transfer of em&ryos from a
'5 year)old #oman #ho had lost her uterus to her ,/ year)old mother #ho #as meno!ausal &ut
still had a uterus. The mother "grandmother" got !regnant in the first cycle #ith tri!lets, all three
em&ryos im!lanting, and ga"e &irth to three healthy grandchildren. This #as !ro&a&ly the most
dramatic single anecdotal e2am!le of the fact that a #oman of any age can &e highly fertile if the
em&ryos transferred to her come from oocytes of a young #oman.+.-
3n fact, the !regnancy rate #ith donated eggs is usually #ell o"er t#ice as high as it is #ith
standard 3:F or ;3FT. The reason for this is that the donated eggs are either coming from
younger, selected donors #ith good o"arian function or are coming from the e2tra oocytes
a"aila&le from #omen #ho stimulated e2tremely #ell and ha"e far more eggs than they need for
their o#n fertili4ation cycle. Thus, it is the "fertility" so to s!ea6 of the o"ary, or the age of the
eggs, that is im!ortant in determining the agerelated infertility of the #oman rather than any
other as!ect of her re!roducti"e anatomy.+$()$'-
3n summary, as the cou!les age, their fertility #anes. This decrease in fertility is clearly caused at
least &y a declining a&ility of the aging o"ary, des!ite continued o"ulation, to !roduce easily
fertili4a&le eggs that #ill result in a !regnancy #ith a normal li"e &irth. The ne2t issue to &e
tac6led is to #hat e2tent the increasing age of the male !artner might also negati"ely affect the
fertility of the older cou!le.
DECLINING SEXUAL FUNCTION IN THE AGING MALE
Although until recently there has &een great contro"ersy o"er the issue of #hether fertility
declines in men as they get older, there has ne"er &een any contro"ersy a&out the decline of
o"erall se2ual function. $* =ith each succeeding decade after the late teen years, there is a
distinct decrease in the a&ility of all men to o&tain erections easily A greater amount of
stimulation is re0uired for o&taining erections, and a longer inter"al is re0uired after orgasm and
e<aculation for another erection to &e achie"ed. Teenage &oys ha"e erections de"elo!
s!ontaneously at the slightest thought of a female com!anion near&y, #hereas men in their late
,(s and 5(s, although 0uite ca!a&le of
great se2ual e2citement, generally need fore!lay to o&tain an erection sufficient for se2ual
relations.
Furthermore, the firmness of the erection in older men, although ade0uate for !enetration, is not
as turgid as measured o&<ecti"ely to that of younger men. Finally, younger men in their early '(s
can often engage in se2ual relations #ithin less than half an hour after ha"ing had a !re"ious
orgasm, #hereas men in their 5(s may ha"e to #ait hours and !erha!s e"en an entire day &efore
&eing a&le to engage in intercourse again. This inter"al &et#een e<aculation and the a&ility to
o&tain another erection is called the "refractory !eriod" and this refractory !eriod clearly
increases #ith aging +see Fig. $-.
3n young men, e"en after e<aculation, the !enis #ill remain firm for some time after#ard,
#hereas in older men the erection &ecomes flaccid fairly !rom!tly after e<aculation. The force of
the e<aculatory s0uirt in young men is often !o#erful and can e<ect the s!erm some distance. The
force of the s0uirt, !ro!elled &y !o#erful contraction of the &ul&oca"ernosus muscles, is much
less in older men than in younger men. Thus, in e"ery measura&le #ay male !otency is clearly
affected &y age.
>umerous scientific studies ha"e &een !erformed to elucidate the reason for the declining se2ual
!erformance noted in men #ith ad"ancing age.+$,)$.- There has certainly &een found to &e a
modest decline in serum testosterone le"el,
along #ith a modest increase in follicle)
stimulating hormone +FSH- and luteini4ing
hormone +?H- associated #ith ad"anced age
in men. 8ut these changes are not great
enough to account for the significant changes
in se2ual function. Furthermore, although the
testosterone le"el does decrease modestly in
men as they get older, it remains #ithin a
"normal" range. 8ecause of the great
"aria&ility of testosterone among all men and
the lac6 of relationshi! of that "aria&ility of
testosterone le"el to se2ual function in men
of "arious ages, there is no good hormonal
e2!lanation,e2ce!t in rare cases, for the
uni"ersal decline in se2ual function in men
associated #ith age.
3t has not esca!ed the notice of sociologists and !sychologists s!eciali4ing in the treatment of
se2ual dysfunction that this declining !hysical se2ual a&ility in men does not necessarily mean a
decline in se2ual en<oyment or a&ility to satisfy the man1s !artner. 3n fact, 0uite ironically, the
fact that as men reach their middle ages and later years they re0uire fore!lay for stimulation as
#ell as intimacy +not clearly a re0uirement for younger men- often leads to #hat is descri&ed &y
the female !artner as an im!ro"ement in the se2ual !erformance of their mate as they get older.
This !sychological irony not#ithstanding, there is an incontro"erti&le decline in all the
measura&le !hysical as!ects of se2ual function in men as they get older, and there is no clear
e2!lanation other than age itself. The more contro"ersial issue to &e discussed in the ne2t section
is #hether the male !artner1s fertility also declines as he gets older.
#igure 1 $he ability o% the vascular spaes to %ill
and create erection declines &ith advancing age
DECREASED SPERMATOGENESIS AND FERTILITY OF MEN ASSOCIATED WITH
INCREASING AGE
3t is #idely "ie#ed that although the female gradually &ecomes less fertile #ith age and
e"entually undergoes meno!ause &et#een the ages of ,5 and 55 years, the male retains his
fertility #ell into old age and does not go through an endocrinological meno!ause. This !oint of
"ie# is in general accurate. Men at middle age do not ha"e hot flashes and dramatic ele"ations of
FSH and ?H associated #ith gonadal atro!hy as #omen do. 3n fact, men ha"e &een documented
in the scientific literature to retain their fertility to as old an age as .,.'( 3t is #ell 6no#n that the
Senior Senator in the US. @ongress, Senator Strom Thurman, fathered a child at age /$ years.
Similarly in animals, &ulls ha"e &een 6no#n to retain their fertility to as old as $. Aears of age
+0uite aged for cattle-.+'$,''- A&undant s!ermato4oa ha"e &een found in the testes of men
undergoing orchiectomy at an e2tremely old age.+'*,',- Thus, it is clear that men do not undergo
a meno!ause similar to #omen, and men in general can &e e2!ected to retain their fertility #ell
into ad"anced old age.
Ho#e"er, there are age)related declines in male fertility and s!ermatogenesis that ha"e only
recently &een studied #ith great scientific care. These ne# findings hel! elucidate some
other#ise difficult to understand cases #here there seems to &e a deterioration in fertility of
occasional men #ho #ere clearly fertile #hen they #ere young, &ut later de"elo!ed "ery se"ere
oligos!ermia, and could no longer get an other#ise fertile, younger #ife !regnant. The 0uestion
isB e"en though men can ha"e ade0uate se2 li"es into an old age, is there a decline in fertility that
!arallels the decline in o&<ecti"ely measura&le as!ects of se2ual function that #e ha"e already
discussed in the !re"ious section.+'5-
3n $./, Cohnson measured daily s!erm !roduction in a grou! of /. men, ages '$ to 5( years, and
com!ared that to a grou! of ,* men, ages 5$ to /( years. '7 The methodology #as a random
selection of such testes o&tained at auto!sy #ith a mor!hologic method of determining daily
s!erm !roduction at the time of death. As might &e e2!ected, there #as a remar6a&ly large
standard de"iation +more than a 5(% "ariation of mean "alue in daily s!erm !roduction from one
man to another-, e"en #ithin the same age grou!. Ho#e"er, if one sim!ly loo6ed at the mean
daily s!erm !roduction of men from the older grou! and com!ared that to the mean of men from
the younger grou!, there #as an a"erage of *(% greater s!erm !roduction in younger men than
in older men. There could &e no dou&t on the &asis of this study that s!erm !roduction declines
significantly #ith age in the human male, e"en though a *(% decline in most men #ould not &e
sufficient to render them infertile if !re"iously they had &een fertile. Aet in some men #ho
started out on the lo#est edge of fertility in youth, a significant enough reduction in s!erm
!roduction could ha"e resulted in se"ere infertility or sterility &y middle age.
The mechanism #here&y age causes a decrease in s!erm !roduction in the men is im!ortant to
understand, &ecause it &ears hea"ily on an understanding of the difference in mechanisms of
s!erm !roduction in men #ho are fertile "ersus men #ho are infertile, and the !ossi&ilities for
treatment. First, #e should re"ie# in a sim!lified fashion the normal stages of s!ermatogenesis,
ho# #e 0uantitate it on testicle &io!sy, #hat stages of s!ermatogenesis are affected &y #hat
hormones, ho# these stages of s!ermatogenesis com!are to the stages of oogenesis in the female,
and ho# oogenesis is affected &y hormones. =e #ill see a remar6a&le similarity &et#een
hormonal stimulation of different stages of s!ermatogenesis in the male as #ell as oogenesis in
the female during each menstrual cycle. This #ill hel! us gain an understanding of the relati"e
refractoriness of s!ermatogenesis to hy!erstimulation #ith hormones. =e #ill then &e a&le to see
ho# age affects s!ermatogenesis, at #hat stage of s!ermatogenesis age has its negati"e affect,
and ho# this #hole !rocess differs in oogenesis.
SIMPLIFIED REVIEW OF NORMALSPERMATOGENESIS AND COMPARISON TO
OOGENESIS
There has &een little clinical literature, if any at all, a&out the com!arison of s!ermatogenesis in
the male and oogenesis in the female. There is a dramatic similarity in the genetic !re!aration of
the egg for fertili4ation +#hich occurs under the influence of FSH and ?H during each monthly
menstrual cycle-, and the changes that early s!ermatogonia go through in the male testes during a
*)month cycle, to result in the release of mature s!ermato4oa. Although the mor!hology and
dynamics of s!ermatogenesis are 0uite com!le2, a sim!lified re"ie# at this !oint #ill hel! to
e2!lain the reduction in fertility found in older men as #ell as de"elo! a &etter understanding of
male factor !ro&lems in younger men and the confusing refractoriness of such male factor
!atients to hormonal stimulation +e"en in se"erely oligos!ermic men #ith lo# or normal FSH
le"els-.
=hen men ha"e lo# s!erm counts or high s!erm counts, it is not &ecause they are ma6ing s!erm
at a slo#er or faster rate. 3t is sim!ly &ecause there are less s!erm &eing made. Dinetically the
rate of s!erm !roduction is constant in any s!ecies. Heller and @lermont first descri&ed the
histology and 6inetics of s!ermatogenesis in the human.+'9- They determined through
radioacti"e tracer studies that the rate of s!ermatogenesis in humans, or in any s!ecies, is al#ays
constant, e"en #hen s!erm !roduction is dramatically reduced. Reduced s!erm !roduction is
al#ays caused &y a reduced num&er of s!erm "on the assem&ly line," &ut not &y any reduced
s!eed of s!ermatogenesis. Therefore, the amount of s!erm &eing !roduced &y the testicle is
al#ays reflected &y #hat is seen at any moment,either in a thin s!ecimen of a testicle &io!sy or a
homogeni4ed s!ecimen of testicular tissue.+'/)*$-
Euantitation of the ste!s of s!ermatogenesis on testicle &io!sy has &een sho#n clearly to
correlate #ith daily s!erm !roduction and s!erm count in men #ho are not o&structed*( +see Fig.
'-. There is no correlation &et#een s!erm count and the num&er of s!erm !recursors such as
s!ermatogonia or !rimary and secondary s!ermatocytes. 3n fact, most infertile men #ith se"ere
oligos!ermia ha"e normal si4e testicles, normal FSH le"els, and large amounts of s!ermatogonia
and s!ermatocytes, &ut a dramatically reduced num&er of s!ermatids, indicating a failure of the
second meiotic reduction di"ision. Most infertile males a!!ear to &e endocrinologically 0uite
normal &ut for some reason ha"e a &loc6 at meiosis, the second reduction di"ision stage, #hich
in the female is e0ui"alent to the release of the second !olar &ody that is stimulated not
hormonally, &ut &y !enetration of the oocyte &y the s!erm.
#igure ' $his graph sho&s the predictable relationship bet&een sperm
count and the number o% mature (ie, Sc and Sd, or simply the number
o% dar) oval dots* spermatids per tubule +hen there is obstruction, the
sperm count is severely and dramatically lo&er than &hat this graph
&ould predict
?et us re"ie# the stages of s!ermatogenesis
no#. At the !eri!hery of the seminiferous
tu&ule are the early dar6 s!ermatogonia. Their
!resence is not hormonally de!endent. The
stages of !roduction of s!erm !roceed in an
orderly fashion from this dar6 ty!e "A"
s!ermatogonia. First the s!ermatogonia
&ecome !ale and then transform into a ty!e
"8" s!ermatogonia +see Fig. *-.
S!ermatogenesis is a !rocess #here&y the
chromatin that #ere originally !resent in the
s!ermatogonia &egin gradually to condense
in!re!aration for the first meiotic reduction
di"ision.
This &egins #ith the de"elo!ment of the ty!e
"8" s!ermatogonia, the !rele!totene
s!ermatogonia, and then the le!totene
s!ermatogonia. This early !rocess is
e0ui"alent to !ro!hase in the stages of
oogenesis.
#igure 3 $he si, stages (-.V-* o% spermatogenesis
in the human -n any one %ocus, ie, in any one
small area o% the semini%erous tubule, there is an
orderly progression %rom less mature to more
mature cells/ $ype A spermatogonia $ype 0
spermatogonia 1, leptotene spermatocytes2 3,
4ygotene spermatocytes2 5, pachytene
spermatocytes2 Sa and Sb, early spermatids2 Sc
and Sd, late spermatids $here is, ho&ever, a
chaotic placement o% these various stages o%
spermatogenesis in a random mi, in humans
rather than in an orderly &ave as in other animals
along the semini%erous tubule $he meiotic phase
o% spermatogenesis occurs &hen the pachytene
(5* spermatocyte divides into t&o early
spermatids
uring the follicular !hase of oogenesis, the !rimordial oocyte is enlarging from a&out '(
micrometers to $*( micrometers in si4e, under the influence !rimarily of FSH. uring this
!rocess ?H rece!tors are !re!ared for .the !reo"ulatory ?H surge. This ?H surge is not merely a
#ay of triggering o"ulation. 3n fact, o"ulation is a relati"ely minor effect of ?H. The ma<or
genetic effect of ?H is to initiate the resum!tion of meiosis, #hich had &een arrested from
infancy at !ro!hase. This is e0ui"alent to #hat ha!!ens in the male as the s!ermatogonia &ecome
transformed into !rele!totene, le!totene, 4ygotene, and !achytene s!ermatocytes. This is a
!rocess #here&y chromosomes are condensing and !re!aring for the first meiotic di"ision.
3n men #ho ha"e no !ituitary function, the mere administration of ?H or human chorionic
gonadotro!in +h@;- #ill &ring s!ermatogenesis u! to this !achytene s!ermatocyte stage &ut does
not allo# meiosis to com!lete. Meiosis cannot &e com!leted in the s!ermatogenic !rocess
#ithout FSH. Ho#e"er, since infertile men #ith se"ere oligos!ermia or a4oos!ermia most
commonly ha"e a normal FSH and ?H le"el, the second reduction di"ision +#hich is the usual
deficiency in infertile men-, does not a!!ear to &e a hormonally de!endent e"ent. This is 0uite
similar to the female #here&y the release of the second !olar &ody re0uires !rior FSH and ?H
!riming &ut is a!!arently not triggered s!ecifically &y FSH or ?H, &ut rather &y the e"ent of
s!erm !enetration.+*'-
3n almost all other animals there is an orderly #a"e of s!ermatogenesis !roceeding along the
seminiferous tu&ule. At any !oint in the tu&ule you can only see one s!ecific stage of
s!ermatogenesis +e.g., s!ermatogonia, early s!ermatocytes, late s!ermatocytes, or !erha!s
mature s!erm-. 3n non!rimate animals, this !roduction of s!erm occurs in an organi4ed
assem&ly)li6e fashion mo"ing along the tu&ule in a histologically defina&le #a"e +see Fig. ,-.
Only in humans and in some ;reat A!es is this !rocess a rather unorderly, chaotic mosaic, so
that different stages of s!ermatogenesis can
&e seen in a helter)s6elter fashion occurring
any#here at any time in any area of the
seminiferous tu&ule.
This chaotic arrangement of s!ermatogenesis
in the human is !art of the e"olutionary
&rea6do#n in s!erm !roduction that accounts
for human males &eing the most inefficient
s!erm !roducers +aside from a fe# ;reat
A!es- in the entire animal 6ingdom. Almost
e"ery animal that has e"er &een studied
!roduces a!!ro2imately '5 million s!erm !er
gram of testicular tissue !er day, #hereas
humans !roduce only a&out , million s!erm
!er gram of testicular tissue !er day.
es!ite this chaotic arrangement of
s!ermatogenesis in the human, ho#e"er, it
has &een !ossi&le to locate s!ecific stages of
#igure 6 A, $he upper %igure demonstrates the
orderly &ave o% spermatogenesis seen in virtually
all animals e,cept the human, &hereby a cut
through any particular semini%erous tubule &ill
sho& only one distinct stage o% spermatogenesis
0, $he lo&er %igure demonstrates the scattered
mosaic arrangement o% the various stages o%
spermatogenesis in humans, &hich does not
proceed in an orderly &ave do&n the tubule -nset
sho&s cross.section
s!ermatogenesis #here the !roduction is deficient in fertile men, in infertile men, oligos!ermic
men, "normal" men, and in aging men. E"en in so)called normal fertile men there is a moderate
&rea6do#n at meiosis. 8et#een the easily discerni&le !achytene s!ermatocyte and the early
s!ermato4oa +or s!ermatid- stage there is al#ays some s!erm loss +see Fig. 5-. This is a highly
significant !henomenon found only in a fe# animals, li6e humans and gorillas, #here the male is
re!roducti"ely "ery inefficient. E"en in the most fertile human males there is a relati"ely large
loss of !otential s!ermato4oa in late meiosis that does not occur in other animals.
3n oligos!ermic men #ho are infertile, this is also the most common stage #here
s!ermatogenesis is deficient. 3t is sim!ly that in these infertile oligos!ermic men, the late meiotic
&rea6do#n is far more se"ere than in so)called normal fertile men. Of course, it is true that there
are a minority of infertile oligos!ermic males #ho ha"e either Sertoli cell only syndrome #ith no
s!ermatogonia, or sim!ly "astly reduced total s!ermatogenesis starting from the s!ermatogonial
le"el. These men generally ha"e an ele"ated FSH. Ho#e"er, they are a distinctly small minority
of the infertile male !o!ulation. Most infertile males #ith se"ere oligos!ermia ha"e a normal
FSH and normal or e"en high num&ers of s!ermatogonia and s!ermatocytes, &ut sim!ly little or
no con"ersion from s!ermatocyte to s!ermatids in the second meotic di"ision.
#igure 7 $esticle biopsy sho&ing normal spermatogenesis $he
dar) small oval.shaped cells to&ard the center o% the tubule are
sperm heads $he larger cells &ith clearly discernible chromatin
strands are the pachytene spermatocytes
SPERMATOGENIC DEFICIENCY IN AGING MEN
Until recently #e had a !oor understanding of the effect of aging on male fertility. 3t #as
assumed that male fertility #as relati"ely immortal &ecause so many elderly men ha"e &een a&le
to im!regnate their #i"es. Ho#e"er, there has &een !re"ious crude data sho#ing a relati"e
decrease in s!erm count, and !ossi&ly fertility, in a certain !ercent of aging men.+'7,*,-
According to an older study of testicle &io!sy sections of men in the third and fourth decades of
life, .(% of seminiferous tu&ules contained s!ermatids, &ut in the fifth to se"enth decades of life,
only 5(% of the seminiferous tu&ules contained mature s!ermatids. 3n men o"er /( years of age
only $(% of seminiferous tu&ules contained mature s!ermatids. Thus, although some
seminiferous tu&ules continue to ma6e s!erm sufficient for im!regnating the female !artner as
late as the ninth decade of life, the !ercentage of seminiferous tu&ules still functioning and
ma6ing s!erm 0uite distinctly decline #ith ad"ancing age.
=hen the s!erm count is reduced in young infertile men, as mentioned &efore, it is usually
closely related to the !ercentage of cell loss during !ost!ro!hase of meiosis +i.e., the second
meiotic di"ision-.+*5- =ith careful, 0uantitati"e e"aluations of testicular histology, s!erm
!roduction rates in humans are usually closely related to the !ercentage of cell loss during the
later stages of meiosis &oth in infertile as #ell as fertile men.+*(,*$,*7)*.-
Ho#e"er, in the aging testicle the situation is different. 3n aging men, the reduction in a"erage
daily s!erm !roduction occurs during meiosis also, &ut it does not occur in the late stage of
meiosis.+,(- Rather, the age)related decline in daily s!erm !roduction results largely from a
&loc6 to further meiosis in the early !ro!hase stage of meiosis. To e2!lain this in a different
fashion, there is no difference &et#een older men and younger men in the num&er of early
!rimary s!ermatocytes !er gram of testicular tissue. Ho#e"er, there is a "ast difference &et#een
older and younger men in the num&er of late s!ermatocytes. This is #hat causes the mean
reduction in num&ers of s!ermato4oa seen in a !o!ulation of older men "ersus a similarly
random !o!ulation of younger men. Older men ha"e a significant reduction 1in !otential daily
s!erm !roduction &et#een the early and the late !rimary s!ermatocyte stage, not late in meiosis
as occurs more commonly in infertile men.+,$,,'-
Thus, the ty!e of maturation arrest that is the most common cause of male factor infertility, and
occurs to some degree in all normal men as #ell, is not the ty!e of maturation arrest that a!!ears
to result from the aging !rocess. Rather, the aging !rocess results in a maturation arrest at a much
earlier stage of s!ermatogenesis, and this seems to &e related to a decrease in 0uantity of Sertoli
cells !resent in older men1s testicles com!ared to that of young men1s testicles.+,*- Since the
!attern of distur&ed s!ermatogenesis in aging men is different from that of other fertile and
infertile !o!ulations, #e are not a&le to state for certain #hether this merely re!resents a
reduction in total amount of s!erm !roduced or a true reduction in the fertility !otential of
elderly men.
For e2am!le, a man #ho in his youth had a s!erm count of 5( million !er cc might !erha!s in his
/(s ha"e a s!erm count of $( million !er cc. 3f there is no s!ecific !athological !rocess other
than aging, it is !ossi&le that his only !ro&lem is a reduction in the num&er of s!ermato4oa and
not a reduction in fertility The ans#er to this 0uestion a#aits the ty!e of massi"e clinical study in
men of "arying ages e0ui"alent to #hat the French re!orted in $./' #ith #omen "arying in ages
undergoing insemination #ith normal donor s!erm. That is, the only definiti"e ans#er to the
0uestion of #hether aging men #ith diminished s!ermatogenesis lose their fertility is to ta6e a
grou! of older and younger men #ho are mated to a homogenous !o!ulation of fertile #omen
and to determine #hether the !regnancy rate or fertili4ation rate #ith 3:F #ould &e lo#er in
those #omen #hose hus&ands #ere older as o!!osed to those #hose hus&ands #ere younger.
Regardless of this !resent lac6 of clarity on the issue of fertility in older men, at least it can &e
said #ith certainty that there is an age)related decline in s!ermatogenesis that might !ossi&ly
result in a moderate decline in male
e is an age)related decline in s!ermatogenesis that might !ossi&ly result in a moderate decline in
male fertility.
d decline in s!ermatogenesis that might !ossi&ly result in a moderate decline in male fertility.
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Introduction
"Midlife crisis" )) this is often the transitional !eriod for men #hen they e2!erience #hat is
termed as the "second childhood". This !eriod usually starts from age ,( to ,5. 3t is also called
andro!ause or male meno!ause &ecause its sym!toms coincide #ith the decrease in a class of
male hormones called androgen. All men are affected, although some to a larger degree than
others. A thorough 6no#ledge of the underlying hormonal and !hysiological changes #ill &etter
!re!are all males to deal #ith this !hase of life.

Ma! R!"roducti#! S$%t!&
The male re!roducti"e regulatory system consists of four com!onentsB
$. the central ner"ous system +@>S- including the hy!othalamus
'. the !ituitary gland
*. the testesF and
,. the end organs #here testicular steroids act.
The master control starts in the hy!othalamus #here gonadotro!in)releasing hormone +;nRH- is
synthesi4ed and is released in a !ulsatile fashion into a "ascular net#or6 that connects the
hy!othalamus to the !ituitary gland. ;nRH !roduction and release is controlled &y numerous
neurotransmitters, including nore!ine!hrine, do!amine, and endor!hins. ;nRH regulates the
release of t#o !ituitary hormones ) the gonadotro!ins ) luteini4ing hormone +?H- and follicle)
stimulating hormone +FSH- in a !ulsitile fashion. ?H regulates the !roduction and secretion of
testosterone &y the ?eydig cells of the testes, and FSH stimulates s!ermatogenesis.
T!%to%t!ron! circuat!% in t'! (ood in %!#!ra )or&%* It can (! (ound to (ot' a(u&in and
%!+ 'or&on!,(indin- -o(uin .SH/G0 1'!r! it i% r!)!rr!d to a% 2(ound t!%to%t!ron!*2 T'i%
i% t'! !a%t acti#! )or&* It can a%o circuat! in a )r!! .un(ound0 )or&3 1'ic' i% con%id!r!d
t'! &o%t acti#!*
Testosterone can e2ert its effects directly on the testosterone rece!tors in cells. 3t can also &e
con"erted to t#o acti"e meta&olites ) dihydrotestosterone +HT- through the en4yme 5 al!ha
reductase, or &y the en4yme aromatase to estradiol.

S$&"to&% o) Andro"au%!
Testosterone, together #ith its meta&olites, is collecti"ely 6no#n as androgens. As a grou! of
steroid hormones, they stimulate the de"elo!ment of masculine characteristics and are
res!onsi&le for male !u&erty characteri4ed &y dee!ening "oice, &roadening shoulders, and
moustache gro#th. The hallmar6 of andro!ause is declining testosterone le"els.
Testosterone le"els &egin to decline #ith age after maturation. This is accom!anied &y the
concurrent a!!earance of a myriad of related !hysiological changes commonly associated #ith
aging. These changes include diminished li&ido, reduced fre0uency of se2 +the "senior slum!"-,
erectile dysfunction, infertility, changes in &ody com!osition, reductions in &ody and facial hair,
and osteo!orosis. Andro!ause is in effect the re"erse of !u&erty.
3n addition, mood in"entory scores indicate that during andro!ause, men re!ort le"els of anger,
confusion, de!ression, and fatigue that are significantly higher than those re!orted &y men #ith
normal testosterone le"els. The a"erage human male &egins to feel some sym!toms of
andro!ause after ,( to ,5 years old, #hich is follo#ed &y ra!id deterioration after the age of 5(.
Many of the sym!toms accom!anying the andro!ause and the aging !rocesses in men are similar
to those of hy!ogonadism. =e can attri&ute at least some of these sym!toms to a decrease in
testosterone le"els, includingB
a. Sexual Functions. Coita )r!4u!nc$ d!cin!% ra"id$ 1it' a-! )ro& a &!an &a+i&a
coita )r!4u!nc$ o) a(out 5 ti&!% "!r 1!!6 at a-! 783 to onc! a 1!!6 at a-! 893 :
ti&!% a &ont' at a-! ;93 and <*; ti&!% a &ont' (!t1!!n t'! a-!% o) ;8 and ;= $!ar%*
3m!otence also increases dramatically #ith age. 3t is rare &efore the age of *(. 3t is
o&ser"ed in / !ercent of !eo!le o"er 5( years old, '( !ercent of those o"er 75 years old,
close to ,( !ercent for those #ho are 9( years old.
&. Body Composition. T'! a&ount o) !an (od$ &a%% in t'! %!d!ntar$ "!r%on d!cr!a%!%
($ a""ro+i&at!$ <9 "!rc!nt )or !#!r$ d!cad! a)t!r t'! a-! o) :9* You coud 'a#!
o%t :9,59 "!rc!nt o) $our !an (od$ &a%% ($ a-! >9* Aging is accom!anied &y a
decrease in lean &ody mass +?8M- and a concurrent significant increase in fat mass.
Although aging itself is an im!ortant determinant of &ody com!osition, !lasma total
testosterone le"els are not correlated to fat mass, regardless of age. The decrease of
muscle mass is highly correlated to free testosterone le"els, #hich !ersists after
correction for age. Testosterone su!!lementation increases muscle mass.
Aging males, li6e hy!ogonadal men, accumulate !referentially "isceral fat. This accumulation is
a ma<or cause of insulin resistance and the atherogenic li!id !rofile. This suggests that o&esity in
elderly men is a more im!ortant health ha4ard than in young men. @ontrary to !o!ular &elief,
clinical trials ha"e sho#n that a lo1 andro-!n %tatu% incr!a%!% t'! ri%6 o) coronar$ art!r$
di%!a%! .CAD0 or at'!ro%c!ro%i%* 3t #as !re"iously &elie"ed that testosterone and other
androgens had the o!!osite effect since men ha"e higher rates of heart disease generally than
#omen. Researchers no# find that lo# androgen le"els #ere associated #ith an increased
incidence of @A. Men #ith @A had a '' !ercent lo#er 1free androgen inde21.
=hile decreased free and total testosterone le"els can lead to increased fat mass, it could also &e
suggested that the decrease in testosterone le"els in the aging male is the conse0uence of an
increase in fat mass. 3n other #ords, t'!r! i% a i6!$ (i,dir!ctiona r!ation%'i"3 t'! !+act
&!c'ani%& o) 1'ic' i% %ti not )u$ 6no1n* O(!%it$ i% a &uti,)actoria di%!a%! t'at a%o
incud!% -!n!tic3 %ocia and "%$c'oo-ica )actor%*

R!"roducti#! Ca"acit$
T#o factors may contri&ute to accelerated hy!ogonadism in aging men. T'! )ir%t i% a %i-'t$
d!cr!a%!d "roduction o) t!%to%t!ron! and t'! %!cond i% an incr!a%! in t'! circuatin-
)raction o) t!%to%t!ron! (ound to SH/G*
Semen analysis in elderly men re"ealed an alteration in s!erm counts in "arying degrees from
normal to increased or a decreased s!erm motility and increase in a&normal s!erm forms. This
finding in older men suggests some degree of !rimary testicular failure.
Ho#e"er, after controlling for age, the correlation &et#een serum testosterone le"els and se2ual
acti"ity #as not significant. This suggests that reduced testosterone le"els are not li6ely to &e
res!onsi&le for se2ual dysfunction and hy!ogonadism in and of itself is an uncommon cause of
im!otence in elderly male.
8ased on these findings, the su!!lementation of testosterone in older men to im!ro"e erectile
function may &e of little &enefit. >e"ertheless, studies ha"e also sho#n that aging men #ith high
se2ual acti"ity le"els ha"e greater !lasma testosterone concentrations than men #ith less se2ual
acti"ity. Although decreases in serum testosterone may ha"e a correlation #ith the diminished
se2ual acti"ity in older men, this effect is !ro&a&ly minor com!ared #ith the contri&utions of
!sychological, social and other health factors such as cardio"ascular diseases. 3ndeed, the
0uestion of #hether or not to use testosterone as a re!lacement strategy in andro!ause use is not
clear)cut.
T'! #a%t &a?orit$ o) &!n do not !+"!ri!nc! a o%% o) t!%to%t!ron! "roduction co&"ar!d to
t'! tota o%% o) !%tro-!n a% occur% in 1o&!n* A% a r!%ut3 t'!$ do not -!n!ra$ !+"!ri!nc!
'ot )a%'!%* Hot flashes in men mostly occur #hen there is a com!lete loss of testosterone such
as during gonadal failures, !ituitary !ro&lems or treatments for ad"anced !rostate cancer.

M!c'ani%& o) Andro"au%!
>umerous researches ha"e &een conducted to e2!lore the mechanism that triggers the decreased
testosterone !roduction #ith age. Theories that ha"e &een !ro!osed includeB
a. Loss of Hypothalamic Sensitivity. r. :. ilman !ro!osed that the ma<or factor in aging
is the dysfunction of the male re!roducti"e homeostat +hy!othalamic ) !ituitary ) testes
a2is-, #hich leads to the !rogressi"e loss of hy!othalamic sensiti"ity to the inhi&itory
effects of testosterone. This loss of hy!othalamic sensiti"ity to the negati"e feed&ac6 loo!
of testosterone has &een confirmed &y a num&er of indirect studies.
&. Testicular Defect Some researchers !ostulated that during aging, there is a concurrent
decreased ?eydig cell1s res!onse to ?H. 3t is li6ely that this loss of ?eydig cell acti"ity is
due to a desensiti4ation of se2 hormone rece!tors due to !rolonged hy!erstimulation &y
chronically ele"ated le"els of ?H +!rimarily- and FSH +&oth of #hich are the result of the
loss of hy!othalamic sensiti"ity-.
c. SHBG Level Increase. ?e"els of total !lasma testosterone are 6no#n to ha"e a
!rogressi"e age)related decrease after the age of 5(. One e2!lanation is that &oth SH8;
le"els increase #ith age and al&umin le"el decrease #ith age. This results in a decline in
&ioa"aila&le testosterone. 3t has &een noted that the decline in &ioa"aila&le testosterone is
greater than the decline in total circulating testosterone. The circulating testosterone,
#hich is &ound to SH8;, is &iologically less acti"e than the free form.
d. Circadian hythm Dysfunction Many !eo!le !ast the age of ,( ha"e increased
difficulty slee!ing. A "ariety of factors such as stress, diet and a distur&ance of the slee!
#a6e cycle can influence slee! 0uality. All these factors !ose as ad"erse effects on other
&iological rhythms, resulting in a dramatic shift of the circadian rhythm of testosterone
!roduction. Testosterone le"els in young men are highest in the e"ening and early
morning. Ho#e"er, this rhythm is greatly attenuated in older men. Therefore, maintaining
a good nights slee! as #ell as a regular slee!)#a6e cycle is a sensi&le a!!roach to
reducing stress and normali4ing our chrono)&iological cloc6.
Other Hormone eficiencies
Other im!ortant hormones that ha"e reduced !roduction le"els from age *( on#ards include
Human ;ro#th Hormone, Melatonin, HEA, and Gregnenolone

Gro!th Hormone
;ro#th hormone le"el in the &ody reaches its !ea6 in the late teens. Then it starts its long decline
at the rate of $, !ercent reduction for each decade thereafter. /$ a-! >93 $ou coud 'a#! o%t a%
&uc' a% >9 "!rc!nt o) t'! a&ount o) -ro1t' 'or&on! in $our (od$*
The gro#th hormone has &een touted as the "eli2ir of gro#th" e"er since r. Rudman !u&lished
his landmar6 study in the Ne& England Journal o% !edicine. r. Rudman ga"e a grou! of
healthy aging adults a high dose, lo# fre0uency !rogram of synthetic gro#th hormone in<ections
for si2 months. The results sho#ed a significant increase in lean &ody mass and a reduction of
&ody fat. r. Rudman concluded that the gro#th hormone in<ections changed the &ody
com!osition consistent #ith $( to $5 years of aging. Since then, many studies and clinical trials
ha"e &een conducted on gro#th hormone.
T'! d!)ici!nc$ o) t'! 'u&an -ro1t' 'or&on! cau%!% &an$ c'an-!% o) %o&ato"au%! 1it'
%i&iar %$&"to&% a% t!%to%t!ron! d!)ici!nc$. The re!lacement of testosterone #ithout
re!lacing gro#th hormone generally does not !roduce ma2imum effecti"e results as &oth
hormones #or6 in synergistically #ith each other to !roduce the &est results.

DH"# $Dehydroepiandrosterone%
HEA, an adrenal hormone, is the most a&undant steroid hormone in the &ody. HEA le"els
!lummet dramatically #ith age, more than any other hormones, after !ea6ing at around age '(.
At t'! a-! o) 593 "roduction !#!% ar! on$ 'a) t'! a&ount co&"ar!d to a-! 79* /$ a-! @93
"roduction !#!% ar! on$ )i#! "!rc!nt o) t'! "!a6 !#!%*
=illiam Regelson, M.. +$..5-, re"ie#ed the effect on male se2ual function as documented in
the ground&rea6ing Massachusetts Male Aging Study. This study in"estigated !rimarily the
se2ual function and acti"ity in men aged ,( to 9(. O) t'! <; 'or&on!% &!a%ur!d in !ac' &an3
on$ DHEA %'o1!d a dir!ct and con%i%t!nt corr!ation 1it' i&"ot!nc!* As HEA le"els
declined, the incidence of im!otence increased. Other re!orted effects of increased HEA
included a reduction in &lood insulin and glucose, increased lean &ody mass and reduction in fat,
increased &one density and lo#ered cholesterol and &lood !ressure. HEA re<u"enates "irtually
e"ery organ system so it "actually ma6es you loo6, feel, and thin6 &etter."

&re'nenolone
Gregnenolone is !roduced in the adrenal gland. 3ts !roduction declines #ith age. Gregnenolone
&loc6s and re"erses many age)accelerating effects of e2cess cortisol.
Gregnenolone is also a !otent neuronutrient that im!ro"es memory, concentration and moods. 3t
enhances &rain function &y facilitating the transmission of ner"e im!ulses so that &rain cells can
communicate more easily. Gregnenolone can hel! to fight de!ression too. 3n one study, !eo!le
#ho #ere not de!ressed had t#ice the amount of !regnenolone circulating in their &loodstreams.
Gregnenolone has the uni0ue a&ility to &alance all other hormones. 3t stimulates the !roduction of
other hormones only #hen they are needed.

(elatonin
Melatonin is !roduced in the !ineal, #hich is located dee! #ithin the &rain. Groduction le"els of
melatonin is reduced during the day and increased in the night. The amount of melatonin
!roduced during the night is ten times the amount !roduced during the day.
Melatonin is also a !otent antio2idant that !rotects the !ineal gland against free radical damage
and hel!s defend our immune system. Researchers no# &elie"e that the !ineal gland also dri"es
the aging !rocess.
As you get older, the !ineal gland !roduces less melatonin. The decline in !roduction is slo# and
gradual after the age of '(. The loss is accelerated after the age of ,(. Melatonin is usually not
recommended for !eo!le under ,( years of age solely for its anti)aging &enefits. This is &ecause
their !roduction le"els of melatonin ha"e not yet declined significantly. Melatonin is commonly
recommended for <et lag and as a slee!ing aid, &ut #e 6no# that it can do much more.
>umerous scientific studies are currently under#ay to study the relationshi! of melatonin and
longe"ity. 3n one interesting e2!eriment, aging mice that recei"ed !ineal gland from younger
mice #as disco"ered to ha"e their life s!an increased &y a third. @on"ersely, young mice gi"en
!ineal gland from old mice had their life s!an reduced &y one)third.

Andro"au%! Tr!at&!nt
). Testosterone eplacement Therapy $TT%
8oth men and #omen !roduce testosterone. The amount !roduced &y #omen is much smaller
and !roduction comes from the adrenal glands. A decline in the testosterone le"el is associated
#ith decrease in se2 dri"e and li&ido in &oth se2es. Testosterone re!lacement thera!y +TRT- re)
energi4es the entire &ody, increases lean muscle mass, and re"erses the fat accumulation and
muscular atro!hy characteristic of aging.
TRT also considera&ly im!ro"es the 0uality of life in men after middle age. The re!lacement of
testosterone may also !rolong lifes!an &y reducing the se"erity of age)associated diseases such
as osteo!orosis and cardio"ascular disease, #hich are among the leading causes of disa&ility and
death.
For men, re!lacement and restoration of testosterone le"el in men to the le"el of a *( to ,( year
old male has sho#n significant anti)aging effects. The normal &lood le"el of testosterone ranges
from $5)$(( mgLd? in #omen and from *(()$,'(( mgLd? in men.
Gre TRT #or6u! should include a com!lete history and !hysical e2amination, together #ith a
&attery of &lood test including male hormonal !rofile and cancer screening test such as GSA to
rule out any relati"e or a&solute contraindications to testosterone re!lacement thera!y.
:arious forms of synthetic testosterone ha"e traditionally &een used. These include oral,
su&lingual, intra)muscular in<ection, and trans)dermal !atches. =hile these synthetic hormones
ha"e &een #idely used #ith &eneficial effects, there are dra#&ac6s to their use.
Oral synthetic !re!arations result in short)term ele"ation and undesira&ly high inter)indi"idual
and intra)indi"idual "aria&ility of concentrations of testosterone. There are also commonly
associated ele"ations of li"er function test and a&normalities at li"er scans. es!ite this, oral
!re!arations still constitute a&out a third of !rescri!tions filled in the United States. Some
common forms are !ure testosterone, methyltestosterone, su&lingual methyltestosterone, and
fluo2ymesterone.
The in<ecta&le synthetic testosterone is esterfied. They are safe, effecti"e, and the least e2!ensi"e
androgen !re!arations a"aila&le. They re0uire an in<ection into a large muscle. 3t is slo#ly
a&sor&ed and last longer. 3t ta6es effect o"er se"eral days or #ee6s. 3n<ections eliminate the
natural daily diurnal rhythm of testosterone !roduction)high at night and early morning and lo#
during the day. Testosterone enanthate and cy!ionate are forms commonly used. They ha"e
com!ara&le !harmaco6inetics. 8oth result in su!ra)!hysiologic concentration of testosterone for
$ to , days after in<ection. A satisfactory regimen is to administer '(( mg of one of these esters
once e"ery t#o #ee6s intramuscularly, &ut a more !hysiologic re!lacement thera!y #ould &e
$(( mg of one of these on a #ee6ly &asis.
Trans)dermal synthetic TRT systems are !erha!s the most commonly used. 3t comes in the form
of scrotal and non)scrotal forms. @linical studies ha"e sho#n that &oth are effecti"e forms of
androgen re!lacement. The ad"antage of the scrotal form is that it !roduces high le"els of
circulating HT due to the high 5)al!ha)reductase en4yme acti"ity of scrotal s6in. 3t also
re0uires sha"ing of the scrotum. 3nade0uate scrotal si4e and adherence !ro&lems are limitations.
S6in irritation does occur in those #ith sensiti"e s6ins. >on)scrotal s6in !atch1s ad"antage is that
the serum testosterone concentration !rofile mimics the normal circadian "ariation o&ser"ed in
healthy young men. S6in irritation is more common, #ith o"er 5( !ercent e2!erience some form
of site reaction sometime during the treatment. Gretreatment #ith corticosteroid creams +not the
ointment forms- has &een sho#n to reduce the se"erity and incidence of s6in irritation #ithout
significantly affecting testosterone a&sor!tion from the !atch.
Androgen re!lacement can ha"e undesira&le side effects, including fre0uent or
!ersistent erections, nausea, "omiting, <aundice, an6le s#elling, or "irili4ation of
female se2ual !artner. 8reast enlargement can also de"elo! as testosterone can &e
con"erted to estrogen "ia the en4yme aromatase. More serious com!lications
include #ater retention, li"er to2icity, cardio"ascular disease, slee! a!nea, and
!rostate enlargement. These ris6s are relati"ely uncommon #hen the dosage is
closely monitored to that found !hysiologically in the &ody.
Androgens are contraindicated in men #ith carcinoma of the &reast or 6no#n or sus!ected
carcinoma of the !rostate. They also should not &e considered in those #ith 6no#n
hy!ersensiti"ity to the !re!aration or in !atients #ith com!romised cardiac, renal, or he!atic
functions.
=hile there is no direct e"idence that lin6 testosterone re!lacement to accelerated !rostate
enlargement, there is a correlation &et#een testosterone treated hy!ogonaldal men and normal
men #ith !rostrate "olume and age.
Grostate cancer is an androgen)res!onsi"e cancer, although there is no e"idence to directly
indicate that testosterone thera!y causes !rostate cancer. 3f !rostate cancer cells already e2ist in
the &ody, the disease may &e stimulated to s!read. Therefore, !re)treatment screening for any
!rostate dysfunction is mandatory. A digital rectal e2amination +RE- and la&oratory test for
!rostate s!ecific antigen +GSA- should &e chec6ed &efore initiation of thera!y and e"ery * to 7
months thereafter. An a&normal RE, an increase in GSA of more than ' ngLdl, or a total GSA of
greater than ,.( ngLdl re0uires further urological e"aluation. Other tests include hemotocrit, &one
density, and !lasma li!ids on an annual &asis.
Results of testosterone re!lacement may not &e e"ident for se"eral #ee6s. 3m!otence may not &e
corrected after se"eral months of thera!y des!ite im!ro"ement in other andro!ause sym!toms.
For these !atients, e"aluation for causes of erectile dysfunction other than hy!ogonadism due to
andro!ause is indicated.
@lose monitoring of serum testosterone le"els should &e carried out for !atients on testosterone.
Other signs, such as acne, increase &reast si4e, and tenderness should &e chec6ed. After one #ee6
or more of trans)dermal TRT, serum testosterone le"els can &e measured a&out $' hours after
!atch a!!lication and dosage ad<usted accordingly. For oral methyltestosterone thera!y, no
assays are a"aila&le to monitor thera!y. For !atients on the in<ecta&le form, nadir testosterone
le"els should &e o&tained * to , months !rior to the ne2t in<ection.
Recently, natural forms of testosterone ha"e &ecome a"aila&le #hich !ossess all the &enefits of
synthetic hormones and little ad"erse side effects. They are a"aila&le from s!eciali4ed
com!ounding !harmacy under the !rescri!tion of a !hysician.
The alternati"es to testosterone include the testosterone !recursors, androstenedione and
androstenediol, #hich are a"aila&le in oral ca!sules or su&lingual s!rays.
=hile testosterone re!lacement is one of the most effecti"e #ays to relief andro!ause sym!toms
and may &e indicated in the aging male #ith documented hy!ogonadism, this hormone should
not &e used in those #ith normal testosterone le"els. Under the care of a 6no#ledgea&le
!hysician, this thera!y is "ery safe for the "ast ma<ority of andro!ause !atients.
*. Gro!th Hormone $hGH%
The 0uic6 #ay to re"erse the declining gro#th hormone +h;H- le"el is &y h;H in<ections. A
!hysician must monitor the in<ections. As #ith all hormones, gro#th hormone can &e fatal if
administered #ithout !ro!er !recautions.
3n !articular, !eo!le #ith e2cessi"e li!ids in their &lood, dia&etes, and a&normal li"er function
must ha"e e2tensi"e medical #or6u! !rior to commencing treatment. The use of gro#th
hormone also re0uires no !re)e2isting dia&etes or cancer. The dose must &e 6e!t to a minimum or
<oint !ains, heart failure or car!al tunnel syndrome may occur. @ommonly used dosage is $ 3U
!er day &y in<ection. This is a lo# dose, high fre0uency !rogram that is 0uite different from the
original study carried out &y r. Rudman years &ac6. Furthermore, for each fi"e to si2 days of
in<ections, there should &e a one to t#o days of rest #here the &ody is gi"en oral su!!lementation
such as secretagogue. The effecti"eness of gro#th hormone thera!y is measured through
monitoring the 3;F)$ le"el in the &lood. This is the meta&olite and mar6er of gro#th hormone. 3t
is customary to try to achie"e an 3;F)$ le"el of *5( mgLdl as the end !oint in an anti)aging
!rogram.
=hile there is little dou&t that gro#th hormone #or6s, its use is not #ides!read due to its high
cost and !ossi&le side effects if not monitored carefully.
3s there a natural #ay of re!lacing our gro#th hormone #ithout drugsM Many !hysicians
!racticing anti)aging medicine &elie"e so. These !hysicians &elie"e in stimulating the !ituitary
gland to naturally increase the release of h;H. Su&stances that stimulate the !ituitary gland in
this manner are called secretagogues. Secretagogues are natural elements and side effects are
rare. The results, though not as significant as in<ections, ha"e &een "ery encouraging. The
re!lenishment of gro#th hormone from a deficient state can lead to an im!ro"ed se2 lifeF s6in
tone and can hel! to &alance other hormones in the &ody including testosterone, HEA,
melatonin, !regnenolone, and !rogesterone.
Other #ays to increase gro#th hormone release endogenously include intense strength training,
cardio"ascular e2ercises, calorie restrictions, and !ro!er inta6e of nutraceutical su!!lementation,
"itamins, antio2idants and amino acids such as glutamine, ornithine, and lysine that acts as a !ro)
hormones.
+. DH"#
Many !eo!le ha"e re!orted more energy, a&ility to handle stress more easily, thin6 more clearly
and generally feel &etter, after recei"ing HEA. Other &enefits include enhanced immunity
+stronger resistance to colds, flu etc- and lo#er cholesterol le"els.
HEA1s a&ility to re<u"enate the immune function is !articularly #orthy of consideration. 3t
&oosts anti&ody !roductionF enhances the acti"ity of monocytes and ma2imi4es the anti)cancer
function of immune cells 6no#n as T lym!hocytes. =hen administered concurrently #ith a flu
"accine, HEA has &een sho#n to im!ro"e the effecti"eness of the "accine in la&oratory animals
and in aging humans.
One interesting note is that HEA is not regulated &y a negati"e feed&ac6 loo! in the &ody. 3n
other #ords, ta6ing su!!lements of HEA #ill not su!!ress the !roduction of these hormones or
cause the adrenal to rest and result in atro!hy from the disuse. Theoretically, no "resting !eriod"
is re0uired, although it is a good !ractice to ha"e a resting cycle of a fe# #ee6s for e"ery fe#
months of thera!y, as #ith all hormone re!lacement.
HEA re!lacement thera!y offers !o#erful health &enefits and is "irtually ris6)free. The usual
starting dose is '5 mg. Men may re0uire a higher 0uantity +u! to $(( mg- #hile #omen may
need less +u! to 5( mg-. The ideal anti)aging strategy is to su!!lement &oth HEA and its
!recursor, !regnenolone. @ommercial HEA !roducts are made from diosgenin, an e2tract from
the Me2ican #ild yam of the "ioscorea family. 8iochemists can con"ert diosgenin to HEA &y
engineering a series of chemical con"ersions, &ut such con"ersion only ha!!ens in the la&oratory
and not in the human &ody. The ingestion of "ioscorea !lant e2tracts cannot !ossi&ly lead to the
formation of HEA in the &ody.
,. &re'nenolone
>umerous studies ha"e sho#n the effects of !regnenolone on the &ody and &rain. 3t &oosts
energy, ele"ates mood and im!ro"es memory and mental !erformance. Gregnenolone also creates
a sense of #ell &eing #hile im!ro"ing the a&ility to tolerate stress. Furthermore, !regnenolone
has a host of ad"antages #hich includes the a&ility to influence cere&ral function, energy le"el,
the female re!roducti"e cycle, immune defenses, inflammation, mood, s6in health, slee!
!atterns, stress tolerance, #ound healing. Ta6ing !regnenolone therefore normali4es and
re<u"enates the entire adrenal cascade.
The normal starting dose is $5 mg, increasing u! to $(( mg for men or #omen. There are
minimal side effects. A la&oratory, although good, is not necessary for doses &elo# '((
milligrams !er day. Gregnenolone should &e deri"ed from a !harmacologically !ure !roduct and
not a yam)deri"ed "!recursor." A "ery safe dose is &et#een '5 and $(( milligrams !er day.
Although !regnenolone has not &een studied as e2tensi"ely as HEA as it is a !recursor of
HEA and since it a!!ears to decline as ra!idly as HEA, !regnenolone should also &e
considered in a com!rehensi"e hormonal re!lacement regimen.
Gregnenolone is &est tested for its a&ility to alle"iate de!ression, im!ro"e moods and enhance
cogniti"e !erformance. 3t also has corticosteroid)li6e anti)inflammatory effects #ithout the <oint)
destroying cata&olic effects of corticosteroids +Regelson, $..5-.
3t is often recommended for anti)aging !ur!oses that &oth !regnenolone and HEA &e ta6en
together. Since some !regnenolone is con"erted into HEA, the amount of HEA inta6e can &e
lo#ered if &oth are ta6en together.
-. (elatonin
One of the causes of the disru!tions of slee!ing !atterns during aging is the reduction in the
nightly release of melatonin &y the !ineal gland. Many !eo!le ha"e disco"ered that &edtime
doses of melatonin restored their a&ility to o&tain a sound and !eaceful night1s slee!.
Melatonin le"els are 6no#n to decline drastically #ith age. Since melatonin and FSH a!!ear to
&e antagonistic in #omen, the same relationshi! may &e true for men. 3t has &een !ostulated that
melatonin may e"en act to normali4e +lo#er- gonadotro!in le"els. 3t is one of the fe# su&stances
that ha"e re!eatedly &een sho#n to e2tend the ma2imum lifes!an of e2!erimental animals.
=hile lo# doses of melatonin +(.5 to 7 grams- act as a natural slee!ing !ill, high doses of
melatonin +'( grams or more- ha"e &een used to fight cancer gro#th.
The e2act dosage "aries greatly &et#een !eo!le. Trial and error is the &est method. A higher dose
does not mean more !otency. Some !eo!le may feel &etter #ith a smaller dose. To nor&aiA!
%!!" and t'! (iococ63 a -ood do%a-! to %tart i% < &- and %'oud (! -radua$ incr!a%!d i)
t'!r! ar! no %id! !))!ct%* A slight disorientation and di44iness may &e e2!erienced for the first
fe# hours after #a6ing u! #hen melatonin treatment is first started. This sensation should go
a#ay after a fe# nights of melatonin use. 3f it !ersists, a reduced dose is recommended.
There are a fe# rules for the effecti"e use of melatonin. Firstly, al#ays ta6e this hormone <ust
&efore &edtime. 3f you ta6e it earlier in the day, it may disru!t slee!ing and #a6ing cycles.
.. /ormali0ation of Hypothalamic Function
The follo#ing su&stances are !ostulated to restore the hy!othalamic +central- or !eri!heral +end
organ- rece!tor sensiti"ity to testosterone. They are not commonly used as an anti)aging
thera!eutic modality due to the lac6 of long)term clinical studies into its effecti"eness.
a. N!urotran%&itt!r &oduation
Alterations of catecholamine neurotransmitters +e!ine!hrine, nore!ine!hrine, do!amine-
as #ell as a changing &alance of the catecholamineLserotonin ratio ha"e &een !ostulated
as the main cause of the loss of hy!othalamic sensiti"ity &y r. ilman. Using selecti"e
drugs li6e MAO)8 inhi&itor, e!renyl and neurotransmitter !recursors such as the amino
acids tyrosine, ?)OGA, and 5)HTG can normali4e this.
&. M!t)or&in
Metformin is an oral anti)dia&etic !rescri!tion drug. 3t is also a "ery effecti"e anti)aging
agent. Metformin acts &y re)sensiti4ing the hy!othalamus to negati"e feed&ac6 inhi&ition
&y steroid hormones. Used as an anti)aging agent, it has &een sho#ed that use in non)
dia&etic !eo!le results in lo#ered cholesterol and triglycerides, reduced glucose, and the
!re"ention of atherosclerosis. Metformin may also increase testosterone le"els &y
normali4ing &lood glucose and insulin le"els. Some !hysician uses !henformin instead.
This is a less effecti"e analog of metformin, #hich has &een sho#n to hel! e2tend the
ma2imum lifes!an of rats and mice.
c. GoatB% Ru!
;oat1s Rue +8alega o%%icinalis- is the her&al !rototy!e of the &iguanide class of
!harmaceuticals that includes metformin and !henformin. 3t is &elie"ed that ;oat1s Rue
#ould ha"e the same effects as Metformin although there is a lac6 of sufficient research
to su&stantiate the claims.
d. Punctur! #in! .Tri(uu% t!rr!%tri%0
Tri&ulus is an her& that has &een used for centuries in 3ndia as a treatment for &oth male
and female se2ual dysfunction. 3t has &een #idely tested for its efficacy in enhancing
s!erm 0uality and mo&ility. Tri&ulus has also &een used to increase li&ido and se2ual
!erformance in e2!erimental animals and men.
Studies ha"e sho#n that tri&ulus administration has resulted in an increase of ?H le"els
&y 9' !ercent and free testosterone le"els &y ,$ !ercent. =hile the e2act mechanism of
action is not 6no#n, studies ha"e sho#n that it enhances s!ermatogenesis &y enhancing
the acti"ity of FSH u!on the Sertolli cells in the testes.
Tri&ulus also seems to stimulate the central ner"ous system directly to increase the
secretion of ?H thus resulting in an increased le"el of testosterone. 3t is also !ostulated
that tri&ulus may directly sensiti4e the ?eydig cells of the testes. These cells in turn
!roduce testosterone in res!onse to ?H.
1. 2ther (ale eproductive "nhancers
a. Yo'i&(!
Aohim&e has traditionally &een used to enhance male !otency and li&ido. 3t has ac0uired
the re!utation of &eing a male a!hrodisiac and is listed in the Ghysician1s es6 Reference
+GR- as such. It act% a% an a"'a,adr!n!r-ic %ti&uant* Ho#e"er, due to it1s
stimulatory !ro!erty, the cardio"ascular system is affected. Sid! !))!ct incud!% incr!a%!
'!art rat!3 'i-' (ood "r!%%ur!3 and n!r#ou%n!%%* Pati!nt% 1it' '$"!rt!n%ion3
'i%tor$ o) '!art attac6 or %tro6! %'oud con%ut a "'$%ician )ir%t (!)or! u%in-
Yo'i&(!*
&. Muira Pua&a
Muira Guama is also 6no#n as "!otency #ood". 3t has long &een used as a !o#erful
a!hrodisiac and ner"e stimulant in South American fol6 medicine. Muira Guama may &e
effecti"e in restoring li&ido and treating erectile dysfunction. >umerous studies ha"e
&een conducted to "alidate this action. 3n one study, '7' !atients #ith decrease li&ido and
!otency dysfunction #ere gi"en $ to $.5 grams of oral Muira Guama e2tract. =ithin '
#ee6s, it #as sho#n that 7' !ercent of the su&<ect re!orted &enefits from Muira Guama.
Unfortunately, the mechanism of action of Muira Guama is not 6no#n, and more studies
are needed to ascertain its mechanism of action.
3. &rostate &rotection
Men o"er ,5 needs to &e a#are of the sym!toms of !rostrate cancer. Some $/(,((( American
men this year #ill &e diagnosed #ith !rostate cancer. *,,((( Americans #ill die from the
disease. Grostate cancer is the leading non)s6in cancer in men.
8enign Grostatic Hy!er!lasia +8GH- is a near uni"ersal disease of aging men. Men o"er ,(
should ha"e an annual digital rectal e2am on their !rostate and men o"er 5( needs to ha"e a
s!ecial &lood test to screen for !rostate cancer.
Gre"ention and enhancement of Grostatic health #ith &otanicals is #idely !racticed in Euro!e
and has &een sho#n to &e more effecti"e than drugs.
ecades of studies and hundreds of clinical studies ha"e sho#n that e2tracts from Sa# !almetto,
5ygeum a%ricanum and Stinging nettle ha"e all demonstrated efficacies #hen used in the
treatment and !re"ention of &enign !rostatic hy!ertro!hy +8GH-.
ue to their multi!le actions, it should &e no sur!rise that #hen these &otanicals are com&ined,
they are e"en more effecti"e than #hen used indi"idually. An estimated .( !ercent of men #ho
ha"e mild to moderate 8GH e2!erience some im!ro"ement in sym!toms during the first four to
si2 #ee6s of thera!y.
Sa# !almetto has &een sho#n to ha"e "ery fe# side effects. Since it does not interfere #ith GSA
le"els, sa# !almetto #ill not hide cancer sym!toms during GSA tests. 8otanical should &e
seriously considered as a first natural alternati"e to drugs for those #ho #ish to alle"iate
sym!toms of 8GH. These &otanicals can also act as a !ro!hylactic for those #ho are 6een to
!re"ent the onset of 8GH. Healthy men a&out to or already in andro!ause should consider sa#
!almetto as !art of a com!rehensi"e anti)aging !rogram.
4. /utritional Supports
Aging is a syndrome of degenerati"e disease characteri4ed &y age related diseases such as
cardio"ascular dysfunction, cancer and arthritis. One of the !rimary causes of aging is o2idati"e
stress from free radicals. Through im!ro!er diet, e2ternal !ollutants, stress of life, our &ody1s
cells are continually &om&arded &y millions of free radicals each day. The degree and the amount
of free radicals !resent in the &ody are related directly to the s!eed of the aging !rocess.
One of the !rimary goals of anti)aging is to sto! the !roliferation of free radicals through inta6e
of food rich in anti)o2idants and antio2idants su!!lements.
W'i! t'!r! i% no !%ta(i%'!d a(orator$ r!)!r!nc! )or t'! id!a inta6! !#! o) antio+idant%
)or anti,a-in-3 &an$ in t'! )or!)ront o) anti,a-in- r!%!arc' ar! ad#ocatin- &uc' 'i-'!r
!#!% o) inta6! t'an t'! R!co&&!nd!d Di!tar$ Ao1anc! .RDA0 %!t ($ t'! Nationa
Sci!nc! Counci* =hile each !erson is uni0ue in his or her re0uirement, the follo#ing daily
inta6e re!resents !art of a common regimen of !re"enting heart disease and cancer, the
com&ination of #hich accounts for more than /( !ercent of all deaths.
9ardiovascular System 5rotection/
Ascor&yl GalmitateB $(( ) '(( mg
?)?ysineB $5( ) '5( mg
?)GrolineB $(( ) '(( mg
AmylaseB $,5(( SD8U
@ellulaseB 5(( E@U
?i!aseB ,/(( 3U
Ascor&ic Acid +:itamin @-B $,((( ) *,((( mg
@oen4yme E$(B *( ) $'( mg
?)@arnitineB 5(( ) ',((( mg
?i!oic AcidB $(( ) ,(( mg
!usculos)eletal System 5rotection/
a. @alciumB 5(( mg
&. MagnesiumB ,(( ) $,((( mg
c. Malic AcidB $(( ) 5(( mg
d. The magnesium to calcium ratio should &e at least $ to $. Some anti)aging researchers are
ad"ocating a ratio of ' to $.
9ancer 5revention/
a. @alcium );lucarateB $(()*(( mg
&. :itamin EB ,(( ) /(( 3U
c. 8eta)@aroteneB $5,((( ) *(,((( 3U
d. ;ra!eseed E2tractB 5( ) $(( mg
e. @itrus 8iofla"onoidsB 5( ) $5( mg
f. SeleniumB '(( ) ,(( mcg
)5. Diet
Geo!le that li"e in the Mediterranean region ha"e one of the lo#est heart attac6 rates in the
#orld. Their diet consists of 5( !ercent com!le2 car&ohydrates +fruits and "egeta&les-, '5
!ercent !rotein +from !lant source li6e tofu and fish li6e salmon-, and '5 !ercent fat +from fish
and oli"e oil-. Their saturated fats, refined car&ohydrates and sugar inta6e are "ery lo#. T'!
M!dit!rran!an di!t i% an !+c!!nt &od! )or anti,a-in- di!t*
Fruits and "egeta&les contain a&undant antio2idants and !hytonutrients. Fish contains essential
fatty acids that are critical &uilding &loc6s of neurotransmitters and hormones. Moderate amount
of !lant)&ased !rotein such as soy&ean is easy on the digesti"e system com!ared to red or #hite
meat.
Our diet should &e fortified #ith digesti"e en4ymes such as amylase, cellulase and li!ase, #hich
may &e needed to digest !rotein and enhance gastrointestinal heath. This should &e !art of the
daily su!!lement inta6e. Reduction of sugar inta6e and a"oidance of cigarette and alcohol are
also im!ortant. Finally, a reduction of calories &y *( !ercent to achie"e 5 to $( !ercent &elo# the
ideal &ody #eight should &e considered.
)). &roper "xercise
E2ercise, in addition to its cardio"ascular &enefits, also increases the le"el of hormones in the
&ody, #hich include gro#th hormone, testosterone, HEA and !regnenolone. Gerforming
strength)training e2ercise is a 6ey com!onent to an anti)aging e2ercise !rogram &ecause of the
a&o"e)mentioned effects. =ithout a dou&t, !+!rci%! i% t'! co%!%t t'in- to t'! anti,a-in- &a-ic
(u!t a% on! can -!t* T'o%! 1'o !+!rci%! r!-uar$ i#! on-!r* 3t1s that sim!le.
Follo#ing an anti)aging e2ercise !rogram incor!orating fle2i&ility training, cardio"ascular
training, and strength training !rogram in a &alanced fashion is the 6ey. o not o"erdo or ignore
any of the three com!onents. Each com!onent is e0ually im!ortant for anti)aging !ur!oses.

Su&&ar$
No &an can !%ca"! andro"au%!* It %tart% at a-! 59 to 58 and a%t% )or <9
to <8 $!ar%* S$&"to&% o) andro"au%! r!)!ct t'at o) '$"o,-onadi%& and
ar! 1or%! a)t!r a-! 89*
T'o%! 1'o !+"!ri!nc! di))icut %$&"to&% durin- andro"au%! &a$ )ind
i)! &or! (!ara(! a)t!r 'or&on! r!"ac!&!nt t'!ra"$ .1it' t!%to%t!ron!3 -ro1t' 'or&on!3
DHEA3 "r!-n!noon!3 and &!atonin0* A 1id! #ari!t$ o) '!r(%3 natura 'or&on!% ar!
a#aia(!*
Hormonal changes are also accom!anied &y an increased ris6 of cancer and heart disease. A
!ro!er diet, regular e2ercise, and ta6ing suita&le nutritional su!!lements are all im!ortant
com!onents in a com!rehensi"e andro!ause strategy.

A(out T'! Aut'or
Mic'a! La&3 M*D*3 M*P*H*3 A*/*A*A*M* is a s!ecialist in Gre"enti"e and Anti)Aging
Medicine. He is currently the irector of Medical Education at the Academy of Anti)Aging
Research, U.S.A. He recei"ed his 8achelor of Science degree from Oregon State Uni"ersity, and
his octor of Medicine degree from ?oma ?inda Uni"ersity School of Medicine, @alifornia. He
also holds a Masters of Gu&lic Health degree and is 8oard @ertification in Anti)aging Medicine
&y the American 8oard of Anti)Aging Medicine. r. ?am !ioneered the formulation of the three
clinical !hases of aging as #ell as the conce!t of diagnosis and treatment of su&)clinical age
related degenerati"e diseases to deter the aging !rocess. r. ?am has &een !u&lished e2tensi"ely
in this field. He is the author of $he #ive 5roven Secrets to 1ongevity +a"aila&le on)line-. He also
ser"es as editor of the Journal o% Anti.Aging Research.
For Mor! In)or&ation
For the latest anti)aging related health issues, "isit r. ?am at 111*DrLa&*co&. Feel free to
email r. ?am at drNr?am.com if you ha"e any 0uestions.
R!"rint In)or&ation
This article may, in its una&ridged, unaltered form and in its entirety only, &e re!rinted and
re!u&lished #ithout !ermission !ro"ided that it is for !ersonal and non commercial education
use only and further !ro"ided that credit &e gi"en to the aut'or3 1it' co"$ri-'t notic! and
111*DrLa&*co& c!ar$ di%"a$!d a% %ourc!. =ritten !ermission from r. ?am is re0uired for
all other use.

O'((' Michael ?am, M.. All Rights Reser"ed.

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