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Biology and Biochemistry of Reproduction and Contraception.

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central carbonium-ion chromophore in XXII or in the
resonance structure IXa. In comparison to the trimethinecarbocyanine V, two effects therefore counteract
methoxybenzthiazole 121 : The color changes from greentinged yellow to red-orange (Table 3).
Table 3. Triazamethinecyanines (XXIV) with different heterocycles A
Ring A in (XXIV)
1,2,4-Triazol-2-yl
1,2,4-Thiodiazol-2-y1
2-Thiazol-yl
2-Bennhiazol-yl
6-Methoxybenztbiazol-2-yl
1
Color
Light fastness on
polyacrylonitrile
green-tinged yellow
yellow
red-tinged yellow
orange
scarlet
2-3
2-3
6
6
7
The triazatrimethinecyanines are surprisingly stable in
acidic aqueous solution, but they are less stable to hydrolysis than the unsymmetrical diazatrimethinecyanines.
Like the azahemicyanines (XXI) they decompose
rapidly in water at pH > 7, giving colorless products of
unknown constitution. They also undergo appreciable
hydrolysis at pH values < 4.
each other in X : The fiypsochromicinfluence of the two
a-nitrogen atoms of the methine chain, which act as
auxochromes, and the bathochromic influence of the
central nitrogen atom, which acts as a chromophore.
If the nature of the heterocycle A in the dye cation
XXIV is altered, then a bathochromic effect is observ.4
The triazatrimethinecyaninesshow a very good affmity
for Orlon@and give bright green-tinged yellow to red
dyeings. The wet fastness is usually excellent. The light
fastness of individual representatives of this class is outstanding. Even in very pale dyeings, individual dyes display light fastness values of 7 to 8. These are the highest
values observed so far with basic dyestuffs [20]. Peculiarly, the light fastness decreases when azole rings with
more than one nitrogen atom are selected for the heterocycle A in XXIV.
We would like to thank Dr. J . D. Kendell of Minnesota
Mining and Manufacturing Co. for valuable criticisms
and the supply of samples.
similar to that observed in the diazahemicyanine series
in the transition from triazole by way of pyridine to 6-
Received, March 9 th, 1962 [A 2W46 IE]
(201 I. R. Geigy AG.. French Pat. 1228047.
Biology and Biochemistry of Reproduction and Contraception
BY DR.
w. JUCHLE
HAUPTLABORATORIUM DER SCHERING AG., BERLIN (GERMANY)
Maturation of sperm and ovum are not autonomous processes. Rather, germ cell activity
is controlled by a regulatory center in the hypothalamus. This assures germ cell maturation,
fertilization, and development of the fetus until birth. Command, functional release, and
feedback take place by humoral pafhs which involve gonadotropin releasers, gonadotropins,
and sex hormones. Even in antiquity, attempts at birth control involved a search for substances which might inhibit the essential physiological and biochemical reproductive processes. This report deals with more recent effortsalong these lines.
I. Physiology of Reproduction
Successful conception requires the presence of male
germ cells capable of fertilization and of female cells
that can be fertilized. These cells are present at certain
ages only. From puberty on, their presence at all times
can be demonstrated only in males, provided the inAngew. Chem. internat. Edit. / Vol. I (1962)1 No. I0
dividual is heaIthy and in a satisfactory nutritional
state [l]. In females, on the other hand, germ cells capable of fertilization are present only at periodic intervals. meir periodicity is reflected in the menstrual
which can be considered as resulting from the
failure of a mature OVUmto have become fertilized.
[I] C.Lutwak-Mann,Vitamins and Hormones 1 6 , (1958).
~
531
Constant maturation of the semen and periodic maturation of ova do not take place autonomously, i.e. independently of what occurs in the rest of the organism.
Rather, the activity of the organs giving rise to the germ
cells, i.e. of the gonads (testes and ovaries), is subject
to central control and exerts feedback effects on all
other central controls.
The hypophysis-hypothalamusconstitutes the regulatory
center of both males and females. The hypophysis with
its anterior lobe is located on or within the base of the
cranium. Its commands are issued in response to orders
that originate in the diencephalon (hypothalamus),
located directly above the hypophysis. The sexual nerve
center is located there. Throughout the entire reproductive system, the preferred path for the transmission of
commands, release or initiation of functions, as well as
feedback, is humoral in nature.
In all likelihood, functional release of pituitary activity
occurs by way of short-chain peptides, the gonadotropin
releasers. The substances released in time by the pituitary are water-soluble protein hormones of as yet unknown structure, i. e. the gonadotropins. The structure
of the substances released by the gonads in response
to the gonadotropins is known: both male and female
sex hormones are steroids. The latter can be classified
in terms of Clg-steroids (estrone derivatives, or estrogens), Clg-steroids (androstane derivatives, or androgens) and Czl-steroids (pregnane derivatives, or gestagens). On the one hand, these sex hormones feed
back information on started secretions in the neuroendocrine system; on the other hand, they induce the
necessary preparation of the germ-cell transporting and
protecting portions of the genital system. In other words,
they cause the secretions of the secondary sex glands to
be ready for ejaculation in the male; in the female they
stimulate development of the endometrium to receive
the fertilized ovum.
The neuroendocrine regulation of the maturation of the
ovum consists of two regulatory cycles [la], which are
interrelated through a feedback mechanism [2].
The pivotal element in both cycles is the hypothalamic
sex center, which is affected by environmental factors,
the autonomic nervous system, and psychological factors, all of which influence sexuality. The regulatory
center is not set at a given degree of sensitivity; rather,
its sensitivity varies throughout life. Thus, in childhood
even small quantities of sex hormones have a pronounced antigonadotropic action; i. e. they inhibit the production of gonadotropins by the anterior pituitary
gland [3,4]. With the advent of puberty, the control
center becomes less sensitive to the sex hormones, until
then probably originating from the adrenal. Even
relatively large doses of sex hormones appear to have
only little antigonadotropic action. This means that
gonadotropin releasers are secreted, and gonadotropins
which are formed in the anterior lobe of the pituitary
[la] W. Hohlweg and K.funkmann, Klin. Wschr. 33, 321 (1932).
[2] R. Wugner, Munchener med. Wschr. 103, 717 (1961).
[3] W.Hohlweg in: 2. Symp. Dtsch. Ges. Endokrinologie,Goslar
1954. Springer, Berlin-Gottingen-Heidelberg.
[4] W. Hohlweg, Wiener klin. Wschr. 71, 445 (1961).
538
are now capable of inducing gonadal maturation and
the production of sex hormones. Sexual maturity
therefore involves a certain sensitivity of the sex center
and the function of a feedback system according to the
following scheme:
Phase 1: Induction of Ovulation
The sex center, freed from the effects of a preceding ovulation
or pregnancy, induces the release in the anterior pituitary of
two gonadotropins, viz. FSH (follicle-stimulating hormone)
and ICSH (the interstitial-cell stimulating or luteinizing
hormone). These in time act to cause a primary ovarian
follicle, which had remained quiescent until now, to mature
into a Graafian follicle; they also induce production of sex
hormones. Estrogens and androgens act on the genital tract
in such a manner as to cause it to develop an optimum milieu
for fertilization (proliferative phase of the endometrium). As
soon as the follicle has released the ovum (ovulation = release
of the mature ovum into the oviduct), these same hormones
inhibit FSH and apparently also ICSH production in the
regulatory center. This blocking reduces gonadotropin
production but does not shut it off completely. From the
point of view of cybernetics, a minimum level of gonadotropin
secretion is necessary to provide residual stimulation (see
Scheme 1). The ovum released from the ovary is capable of
being fertilized for 12 hours. In contrast, semen released
remains viable for up to 72 hours following coitus.
endogenous and
exogenous factors
[
/
FSH and ICSH releasers
.I ,#
I..,,,.:::::"'
..
anterior
ovary
:z
:a
'*
:z
iE
... ...
... ...
... ...
1
ta
.
I
~
estrogen;
A
androgens
j .y
. c
:&
:0
is
genital tract,
secondary sex organs
Scheme 1. First regulatory cycle: Ovulation phase (maturation and
rupture of follicle, development of endometrium).
............_
t
stimulation
inhibition
FSH = follicle stimulating hormone
ICSH = interstitial-cell stimulating hormone
--+
Phase 2: Preparation f o r Nidation
The rise in estrogen level in the blood in Phase 1, in addition
to causing the temporary inhibition of FSH and ICSH, also
causes the release of a third gonadotropin, LTH (luteotropic
hormone). Under its influence the cavity of the ovarian
follicle becomes transformed into the yellow body or corpus
futeum. The ICSH had already initiated this development at
the end of Phase 1. LTH induces and temporarily maintains
the production of estrogens and gestagens in the corpus
luteum. Gestagens and estrogens act to provide the ovum
with optimum paths in the oviduct, as well as optimum
nutritional and nidational conditions in the uterus (transformation and secretion phases of the endometrium). Moreover, they block in the center the release of FSH and of
ICSH and, increasingly, that of LTH (see Scheme 2). If the
ovum remains unfertilized, the corpus luteurn loses its function. Functionally this means: a) desquamation of the
endometrium that was ready for nidation (menstruation or
monthly period); on the average this occurs 28-30 days
after the previous menstrual period; b) restarting of the
Angew. Chem. internal. Edit.
I
Yol. I (1962) No. 10
functions of the firsr regulatory cyc!e, leading to another
ovulation, which normally occurs 12-14 days after the
beginning of the past menstrual period.
.:; . .. .
zl
ell
I
+
ovary
"
. .
:.:-
1
,1
progesterone
genital tract, secondary
1
Scheme 2. Second reguiatory cycle: Preparation for nidation
(formation of corpus luteurn, maturation of corpus h t e m ,
transformation of endometrium; if fertilization does not occur:
corpus luteurn degenerates, endometrium is desquarnated =menstruation).
--+ stimulation
.... _..9..inhibition
LTH = luteotropic hormone
In addition to the regulatory mechanisms outlined so
far, antagonistic relations between estrogens and gestagens may exist in the ovary [4a, b]. Similarly, ovary
and genital tract seem to form a regulatory cycle in
which ovariogenic steroid metabolites, after passing the
uterus, act synergistically with the ovary function
during the first half of the second phase and antagonistically during its second half [4c]
Phase 3 : Pregnancy
If fertilization has occurred, the fertilized ovum will produce
within a few days, i. e. before nidation, choriogenic gonadotropic hormone (HCG), which maintains the function of the
corpus luteurn, perhaps by preventing the release of LTH
from ceasing. A direct effect of HCG on the ovary cannot
be excluded. This then inhibits the functioning of the first
regulatory cycle ( i . e . the cycle is at rest during pregnancy).
In the course of pregnancy, gestagens and estrogens are
formed primarily by the placenta, which can be considered
as a n accessory organ of the embryo or fetus. These in turn
affect the metabolism of the maternal organism, cause the
mammary glands to develop, and protect the uterus and its
content from the labor-inducing activity of the oxytocin
secreted by the hypothalamus (see Scheme 3).
I
hypothalamus
I
progesterone
HCG
1
.
uterus with
embryo (placenta)
Scheme 3. Phase 3: Pregnancy.
+
stimulation
inhibition
LTH = luteotropic hormone
HCG = choriogenic gonadotropin
[4a] Fr. Hofmunn, Geburtsh. Frauenheilk. 22, 433 (1962).
[4b] S. Kullunder, Acta endocrinol. 38, 598 (1961).
[4c] I. W. Rowlands, J. Endocrinology 24, 105 (1962).
Angew. Chem. internat. Edit. Vol. 1 (1962) No. 10
In Phase 2, progesterone and estrogen lead to an active
secretion on the part of the endometrium [5]; the latter
is ready for nidation but cannot effect it under the influence of progesterone alone. A temporary rise in the
estrogen levei, due to estradiol secreted by the corpus
luteurn, releases histamine and initiates the deciduous
reaction of the uterus 151. The simultaneous rise in cytolytic! activity in the lumen of the uterus enables the
trophoblast, i.e. the fertilized ovum in its early developmental stage, to become embedded in the adjoining
endometrium, which has been growing outward as a
decidua. This process completes nidation [5].
In addition to this well regulated sequence of ovulation,
it appears to be possible that ovulation can be induced in sexually mature individuals at other times by
nervous stimuIation [5a-c].
So far, similar phaselike processes involving regulation
and feedback have not been observed in human males.
Nevertheless, they may well occur, as is known from
animal studies, In any event, there is a feedback-controlled equilibrium in males between gonadotropism and
sex hormone production: high doses of sex hormones inhibit FSH and ICSH in the regulatory center; these
latter gonadotropins in turn induce spermatogenesis.
LTH does not appear to have a function in the male. It
is uncertain whether the androgens formed in the testes
are necessary for sperm maturation in situ [4] or whether
they are needed only for the formation of secretions
in the accessory sex organs (prostate gland, seminal
vesicle) [*I. It should be added that, morphological
maturity notwithstanding, the sperm cells formed in the
testes are sterile until they undergo several weeks of
maturation in the epididymis; a functional ejaculate
contains only mature sperm from the epididymis.
II. Biochemistry of Conception
It is characteristic of the sperm cell that it does not obtain its energy for life and motility from aerobic respiration but from anaerobic glycolysis [6, 71. Sperm cells
do possess a complete cytochrome system which would
permit them to use oxygen directly [8,9, 151. However,
151 M. E. Shelesnyak in: Proc. Sixth internat. Conf. Planned
Parenthood. London 1959, p. 151.
[5a] W. Bickenbuch, G. K. Boring, and C. Hossfeidf, Arch.
Gynakol. 192, 412 (1960).
[5b] W. Foellmer, Arch. Gyntikol. 194, 355 (1961).
[Sc] J. Amreich, Wiener med. Wschr. 112, 9 (1962).
[*I The similarity in the neuroendocrine regulation of sexual
activity that prevails in the higher vertebrates has made these the
preferred models of study. Results obtained and observations
made there are frequently transferred to man without regard for
their species-specificity. This is not valid. Similarly, our knowledge of biochemical events is largely derived from experiments
with animals. It appears more justifiable to apply these results
to human studies, at least until reactions have been found that
.are specific for man.
[6] T.Mann in: Mammalian Germ Cells. Ciba Foundation Symposium. Little and Brown, Boston 1954, p. 1.
171 T. Mann: The Biochemistry of Semen. Wiley, New York 1954.
[8] H. Elfrmun in Egle E.T.: Studies on Testes and Ovary, Eggs
and Sperm. Thomas, Springfield, Ill., 1952, p. 26.
[9] T. Mann, Biochem. J. 48, 386 (1951).
539
they behave like anaerobic mnlignant tumor cells [6,10,
111. They differ from the latter, however, in being
anaerobic not because of a mutation involving a loss of
potential but by virtue of having adapted to the milieu
of fertilization, which is poorly supplied by the vasculature and hence poor in oxygen [12-151. Moreover,
as a result of the action of estrogens, the metabolism of
the female genital tract is largely anaerobic and glycolytic [16-211.
It is in such a milieu that the sperms must travel a considerable distance, approximately 2000 times their own
length [22]. Motility, length of life, and fertility of the
sperm are therefore at a maximum under anaerobic conditions and are considerably less so under aerobic conditions [7,10,23-281. The anaerobic source of energy is
fructolysis. In addition, energy may be generated by
oxidation of lactic acid and intracellular plasmalogens,
if the very low oxygen pressure allows such oxidations
to take place [28a].
The metabolism of the maturing sperm in the epididymis
is less glycolytic than that of sperm in the ejaculate [29].
Apparently, enzymes occur in seminal glands and the
prostate which cause uncoupling of the cytochrome and
phosphorylating systems.
Conceivably, the ability t o obtain energy by way of oxidative
metabolism is of more significance for fertilization [30].
Nevertheless it seems doubtful that the observation made on
a phylogenetically primitive animal cell (sea urchin egg) also
applies t o mammalia. In mammalia, fertilization and initial
development of the fertilized ovum through nidation are
probably also mainly anaerobic. Only when the fertilized
ovum has become implanted in the uterus is its oxygen supply
assured. This in turn makes aerobic metabolism possible.
The metabolic processes that accompany ovulation in
the female genital tract serve two purposes: they induce
[lo] J. MacLeod, Amer. J. Physiol. 118, 512 (1943).
[Ill T. Mann, Nature (London) 156, 80 (1945).
[I21 R. S. Hotchkiss: Etiology and Diagnosis in the Treatment of
Infertility in Man. Thomas, Springfield, Ill., 1952.
[I31 J. MacLeod, J. gen. Physiol. 34, 705 (1951).
[13a] M . Kerly, Biochem. J. 31, 1544 (1937).
[14] R . Moricard, Nature (London) 165, 763 (1950).
[I51 R . Morirard in: Mammalian Germ Cells. Ciba Foundation
Symposium. Litlfe and Brown, Boston 1954, p. 187.
[16] W. Dirscherl, H . Schriefers, and H. Brehrer, Acta Endocrinol. 20, 181 (1955).
[I71 W . Eschbach, Arch. Gynakol. 187, 337 (1956).
[18] W. Eschbach and E. Negelein, Arch. Gynlkol. 188,84 (1956).
[I91 M. Kerly, Biochem. J. 31, 1544 (1937).
[20] V. M . Stuermer and R . J. Stern, Amer. J. Obstetr. Gynecol.
63, 359 (1952).
[21] 0. Walaas, E. Walaas, and F. Loken, Acta endocrinol. 10,
201 (1952).
[22] S. ff. Sturgis, Fertil. Sterility 7 , 468 (1956).
[23] D . W. Bishop in: E. T. Engle: Studies on Testes and Ovary,
Eggs and Sperm. Thomas, Springfield, Ill., 1952, p. 95.
[24] E. C. Hughes, Amer. J. Obstetr. Gynec. 49, 10 (1945).
[25] H. A . Lardy, D . Ghosh, and G. W . E. Plant, Science (Washington) 109, 365 (1949).
1261 J. MacLeod, Fertil. Sterility 7, 368 (1956).
[27] G. W . Salisbury and N . L . Vandemark, Nature (London) 180,
989 (1957).
[28] H.Shapiro, Physiol. Zoology 22, 218 (1948).
[28a] T. Mann, Schwejz. Arch. Tierheilk. 103, 359 (1961).
[29] I. G. White and R. G. Wales, J. Reprod. Fertility 2, 225
(1961).
[30] M . Gross, Fertil Sterility 12,245 (1961).
540
anaerobiosis and produce optimum conditions for the
sojourn of the sperm in the tract and for fertilization.
Under the influence of estrogens the cervical mucus becomes more liquid and increases in quantity, and its
NaCl content increases. This facilitates penetration and
survival of the sperm. The pH becomes more alkaline
[30]. The plycolytic metabolism becomes more intense
as the endometrium proliferates, and reaches its peak
at the time of ovulation [30]. Simultaneously, estrogens
increase the activities of the following enzymes: alkaline
phosphatase [31-351, adenosinetriphosphatase [36, 371,
p-glucuronidase [32], sulfatase [32], serine aldolase [40],
peroxidase [42], hexokinase [22], and various dehydrogenases [42,43]. This milieu [44] possibly induces the
so-called capacitation of the sperm. This term refers to
a maturation process of the sperm that occurs in utero
and without which fertilization does not occur [30].
In the secretory phase, which is under progesterone
domination, oxidative glycolysis is again predominant.
Acid phosphatase [45], succinic dehydrogenase [461,
lactic dehydrogenase [47], and carbonic anhydrase [48]
occur in high activities. Whereas estrogens cause glycogen storage [49-511, progesterone leads to glycogen
secretion [24]. In the secretory phase, sperm capacitation
does not take place and the reduced amount of toughened cervical mucus becomes again an agglutinincontaining barrier warding off sperm [30].
Sperm agglutinins, which effect head-to-head agglutination of spermatozoa, are always found in the genital
tracts of both men and women. Though they have similar action, they appear to differ in the two sexes [521.
They occur in the secretions of the sperm glands in
males but are neutralized there by epididymal and
[31] W . B. Atkinson and E. T. Engle, Endocrinology 40, 327
(1947).
[32] J. E. Hall, Amer. J. Obstetr. Gynecol. 60, 212 (1950).
[33] G. T. Hedberg, Gynaecologia 129, 239 (1950).
[34] H. Leeb and U.Ploberger, Enzymologia 16, 3 17 (1954).
[35] H. G. Sturz, Stanford med. Bull. 11, 210 (1953).
[36] A . Csapo, Amer. J. Physiol. 162, 406 (1950).
[37] H . W . Jones, Jr., R . Wade, and B. Goldberg, Amer. J. Obstetr.
Gynecol. 64, 1118 (1952).
[381 W . H . Fishman, J. biol. Chemistry 169,7 (1947).
[39] M . Hayashi, K. Shimoda, K . Ogata, T. Takamori, T. Shirogama, and 0. Kawasi, Acta Histochem. 3, 277 (1957).
[40] A. Herranen and G . C. Mueller, Biochem. biophysica Acta
24, 223 (1957).
[41] F. V . Lucas, H . A . Reufeld, 1. G. Utterbark, A . P. Martin, and
E. Stotz, J. biol. Chemistry 214,775 (1955).
[42] A . T, Bever, J. T. Velardo, M . A , Telfer, F. L. Hisaw, Jr., and
C. M . Goolsby, Fed. Proc. 13, 13 (1954).
[43] C. G. Rosa and J . T. Velardo, Ann. N.Y. Acad. Sci. 83, 122
(1959).
[44] D . Olds and N.L. Van Denmark, Fertil. Sterility 8,345 (1957).
[45] B. Goldberg and H . W . Jones, Jr., Obstetr. Gynecol. 7, 542
(1956).
[46] M . L . Telfer and F. L. Hisaw, Jr., Acta endocrinol. 25, 390
(1957).
I471 A . T. Bever, Ann. N.Y. Acad. Sci. 75,472 (1959).
I481 C. Lutwag-Mann, J. Endocrinology 13, 26 (1955).
[49] B. Lapan and M . M . Friedman, Amer. J. Obstetr. Gynecol.
59, 921 (1950).
[50] H . W. Payne and J. P. A . Lafour, J. din. Endocrinol. 15,
1106 (1955).
[51] 0. Walaas, Acta endocrinol. 10, 175 (1952).
[52] P. E. Lindahl and A . Nilsson, Biochim. biophysica Acta 25,
22 (1957).
Angew. Chern. internat. Edit. f Vol. 1 (1962) ] hro.10
prostatic antiagglutinins. Antiagglutinins occur in the
female genital tract at the same time as estrogen secretion is stimulated by follicle maturation.Their maximum
concentration occurs in the fluids of the follicles and
oviducts [52]. Both ova and spermatozoa are bathed by
fluids that contain antiagglutinins. Thus protected from
clotting, a spermatozoon, thanks to its mobility and its
hyaluronidase activity, can begin its migratioil through
the granulosa cells surrounding the ovum, passing
through the intercellular spaces of the cellular corona
about the biochemistry of or the optimum conditions for
this process [53a]. After ovulation the egg cell is protected from clotting with coagulating plasma by a heparin-like substance 153b]. In the Fallopian tube the egg
cell awaits the sperm cells. Survival, fertilization and
transport of the egg towards the uterus as well as development of the embryo depend on different estrogengestagen relationships the occurrence of which corresponds in time exactly to the necessity for different
optimum conditions [53c]. This is true in particular for
Table 1. Contraceptive plants and minerals used in antiquity
Mode of
application
Origin or area
where used
Authors
Plants or Plant Products
Ancient Greece
Soranus (Sorani Ed.
Ermerins, Traj. ad Rhen., 1869)
Cedar resin
vaginal
Honey
vaginal
Artemisia arborescens
(rue, mugwort, or wormwood)
Crocus sativus (crocus)
Ferida opoponax
Laurel
Nettle seeds
Myrrh
Peony roots
Peucedanum officinaiis
Ruta graveolens
Cypress fruit
vaginal
Artemisia arborescens (see above)
Cheirunrhus cfieiri (wallflower)
Lithospora purpureocoeruleum
vaginal
oral
oral
Ancient Greece
Dioscorides 1601, cited by [591
Aspidium filixlmas
Pteridium aquilinum
oral
oral
Ancient Rome
Pliny (Plinii Historiae mundi,
Basel 1554, LXXVIII, CIX,
Centaurium majus (centaury)
oral
Byzantine,
6th century A.D.
Aetu Amidensis, Libri med.
sedec.. Venice I534
Ammi copticum L .
Ammi visnaga
Aristolochia
Rura graveolens (see above)
Veratrum album (gerber)
oral
oral
oral
oral
oral
Byzantine
7th century A.D.
Pauli Aeginetae Medici
Opera, Lugduni 1551, p. 233
Anchusa finctoria(ox-tongue)
oral and vaginal
Arabian,
13th century A.D.
Artemisia arborescens (see above)
Epimedium alpinum
Gummi ammoniacum
Iris $orentinu (sword lib)
Juniperus sabina (juniper)
Lupinus termes (lupin)
Pinus cedrus (cedar)
Sesamum orientale (sesame)
Seseli tortuosum (sessil)
Stachys germanica (hedge nettle)
in bath
oral
vaginal
Oral
oral
oral
vaginal
Ebn Bailhar, (Sonfheimer's
translation of Collectio
magna, 1840)
Ancient Greece
Hippocrates [541
Soranus
Soranus and Dioscorides [a01
Aneient Greece
Hippocrates 1541, cited by [59]
oral
oral
oral
oral
vaginal
oral
oral
vaginal
vaginal
p. 485)
-
+'
oral
oral
perals
vaginal
vaginal
radiata and through the thick mucoprotein membrane
of the zona pellucida. The sperm cell then remains in the
perivitelline space for a short time. There it is protected
from other sperm cells, which are kept from penetrating
the outer layer of the ovum a9 a result of an unknown
biochemical block. Finally the sperm penetrates into
the cytoplasm of the ovum [53].
Although fertilization in vitro has repeatedly been
achieved, it is not yet possible to give exact information
[53] M.C. Chang in: Proc. Sixth internat. Conf. Planned Parenthood London 1959, p. 129.
Angew. Chem. internat. Edit. 1 Yol. 1 (1962) No. 10
the stage when the embryo reaches the uterus and nidation starts: a short-time increase in estrogen concentration [53d] makes possible the contact between the embryo and the gestagen-primed endometrium. The embryo is lured by the resorptive activity of the endome[53a] J . M . Bedford and M . C. Chang, Nature (London) 193,
898 (1962).
[53b] J. E. Stungroom and R . de G. Weevers, J. Reprod. Fertility
3, 269 (1962).
[53c] E. S. E. Hafez, J. Reprod. Fertility 3, 14 (1962).
[53d] A. Psychoyos, C. r. hebd. Seances Acad. Sci. 253, 1616
(1961).
541
trium [53e]. Under the influence of histamine [5], heparin [53f], and acetylcholine [53g] a deciduoma develops
at the point of contact, which is similar to granulation
tissue and which finally surrounds the embryo.
The plant materials listed have not only an abortive
but also seem to have a clearcut contraceptive action.
Table 2. Contraceptive plants [S91
Species
Mode of
application
Geographical
Area
Geranium pratense
Juniperus sabina
Laihraea squamaria
Lycopodium annotinum
Nerium oleantfer L.
Taxus baccaia L.
oral
oral
oral
oral
oral
oral
Siberia
Central Europe
Russia
Russia
Balkans
Europe
III. Contraceptive Agents
Contraceptivesare substances used before or after coitus
in order to inhibit fertilization or further development of the fertilized ovum. They are intended to
suppress germ cell maturation or to keep the germ cells
from being fertilized, or to inhibit as soon as possible the
further development of the embryo. Such agents should
not interfere with libido or the inclination to have coitus.
When no longer used, there should be no further interference with the development of healthy germ cells.
Contraceptives occupy a central role in birth control
measures, whether they are taken on an individual basis
for the purposes of family planning, on a community
basis (e.g. inIndia andchina) or to reduce the frightening rise in the number of illegal abortions.
Long surrounded by taboos, the discovery and testing of
contraceptives in the past was mostly empirical. Transmission of such knowledge was a matter of tribal or
family custom. Hence the knowledge of effective principles frequently was restricted either to certain areas or
in the number or kinds of people involved. Only in recent
times have medicine and biology begun to devote attention to contraceptive agents.
1. Historical and Ethnological Aspects
The writings of the Hippocratic physicians already contain detailed indications for contraceptives and directions for contraceptive activities [54]. Though making
no claim to completeness, Table 1 lists minerals and
plants which the ancients described as contraceptives.
They culminate in a “patent medicine”, mentioned
several times by Hippocrates; a single ingestion is said
to have produced sterility lasting for one year [54].
Named p o u , its constitution and action are unknown.
The following compounds have been implicated :
CuSO4, FeSO3, or FeS04; all of these have chronic
toxic efforts.
Several detailed publications summarize on a worldwide basis plant materials used for contraceptive purposes [55, 581. These, together with data from Lewin’s
book “Abortion with Poisons” [59], are shown in Table 2.
[53e] R . Vokaer and F. Leroy, Amer. J. Obstetr. Gynecol. 83,
141 (1962).
[53fl C. A . Finn and P . M. Keen, Lecture, Annual Conference
SOC.Study of Fertility, London 1962.
[53g] Y. Chambon, C. r. SOC. Biol. (Paris) 155, 1351 (1961).
[54] Hippocrates: Opera omnia. Ed. van den Linden, Lugd. Bat.
1665.
[55] R . D . C. Casey, Indian J. med. Sci. 14, 590 (1960).
1561 R . D . C . Casey, Indian J. med. Sci. 15,431 (1961).
[57] H . De Laszlo and P. S . Henshaw, Science (Washington) 119,
626 (1954).
[58] R. H . Dreisbach, cited by [56].
[59] L . Lewin: Die Fruchtabtreibung durch Gifte und andere
Mittel. 4th ed., Georg Stilke, Berlin, 1925.
542
As opposed to the large number of supposedly or actually contraceptive plant species, only few plant materials are known to be effective on the basis of clinical
or experimental studies (Table 5). Chemically they are
mostly ill-defined. A systematicsearch for such materials
is made difficult by numerous imponderables. Thus the
content of the active ingredient varies with location,
season of harvest, storage, portion of the plant used,
and methods of preparing and storing the extract. So far,
elucidation of structure and synthesis of contraceptive
plant materials have been achieved in only one case: mxylohydroquinone was extracted from peas, purified and
tested (cf. Table 5). The application of plant materials
is further restricted by toxic side-effects; it is not yet
clear whether these must be attributed to impurities or
to the contraceptives themselves.
2. Mechanism of Action and Structure
of Modern Contraceptives
Two classes of contraceptives are differentiated :
a) materials that act selectively on either male or female
germ cells or on their stages of maturation, or those
which act on the fertilized ovum;
b) materials that affect other physiological or biochemical processes concerned with conception.
In the following, regardless the footnote on p. 539,
results of animal studies will also be considered, even
where their results cannot be applied to man. This is
done to provide a measure of the extent of pertinent
studies.
a) Materials that act selectively on either male or female
germ cells or on the fertilized ovum
or) Spermatozoa (see Scheme 4)
With the exception of spermicidal materials (Table 4),
the only promising compound for human application in
this group is bis(dichloroacety1)diamine. It causes reversible but as yet unexplained arrest of spermatogenesis
in the testes [61]. In contrast to what happens when
derivatives of nitrofuran are taken, which have a similar
effect, the administration of effective doses of bis(dichloracety1)diamineis without side effects [61].
[60] Dioskorides: Comm. ab Eguatio. Veneto 1516.
[61] C. G. Heller, D. J. Moore, Y . Clermond, and C. A . Peulsen,
43rd Meeting endocrinol. SOC.,New York 1961. No. 37, p. 21.
Angew. Chem. internat. Edit. 1 Yol. 1 (1962) / NO.10
The cell and mitotic poisons listed in Table 3 are very
toxic, just as are the antimetabolites. Because of a special
characteristic of spermatogenesis, these compounds may
nevertheless find application in minimal doses: mitosis
in the course of spermatogenesis, including meiotic division, which reduces the number of chromosomes to half,
Table 3.
takes place very slowly. Hence even minimal doses of
these compounds may have an optimum period in which
to act [62].
The azoospermia due to cadmium can be overcome by
the simultaneous administration of zinc. Apparently,
cadmium acts as a competitive enzyme inhibitor [62].
Contraceptives with selective action on either male or female germ cells or on the fertilized OVUI
Agent
Cadmium salts
Selenium
Bis(dichloroacety1)diamine
Cell Poisons
BAL derivatives
Ethyleneimino compounds
Sulfuric acid alkyl esters
( e .g. Myleran)
Nitrofuran derivatives
2-Chloro-2-acetylthiophene
Triethylenemelamine
6-Azauridine
Mitotic Inhibitors
Colchicine (and derivatives)
Category
Effect on
spermatozoa
Ref.
Category
Effect on ova
Category
iffect o n
ertilized ovum
D
mevent
mplantation
)f fertilized
)vum in
items
-
destroy male germ
cell epithelium
inhibit
spermatogenesis
Ref.
I651
damages ova
inhibits
spermatogenesis
kill ova
I851
inhibit spermatogenesis
D
D
D
-
inhibit
spermatogenesis
D
D
D
Methylcholanthrene
MER-25
kill fertilized
ovum
<ill fertilized
wum
D
[80-821
Podophyllotoxin
damages ovum
in tube,
inhibits
fertilization by
estrogen
antagonism
inhibits
spermatogenesis
[91-931
D
inhibit spermatogenesis
inhibit spermatogenesis and
sperm maturation
in testes and
epididymis
a-Aminopropionitrile
Antimetaboiites
Ethionine
:for symbols see caption to Scheme 4)
1851
[94-961
1971
L98.991
kill fertilized
ovum
199- 1031
t1Wl
11051
170.77
86-9C
-
1831
D
D
6-Mercaptopurine, thioguanine
Aminopterine (folic acid
antagonist)
Aniibiorics
Azaserine
kill fertilized
ovum
D
Diazooxonorleucine
D
DiazoacetyIserine
D
kill fertilized
ovum
I 1061
[95,107]
193.99,
106- 1101
[70,99, 1 1 I ]
11121
Spermicidal Agents: see Table 4
[62] T . Mann: Proc. Sixth internat. Conf. Planned Parenthood.
London 1959, p. 122.
[63] M. Allanson and R. Deanesly, J. Reprod. Fert. 2, 510 (1961).
[64] A. B. Kar and R . P . Das, Acta biol. med. germanica 5, 153.
(1 960).
[65] A. B. Kar, cited by 1561.
[66] J. Parizek, J. Reprod. Fertil I , 294 (1960),
[67] J. Freund, M. M. Lipton, and G. E. Thompson, J . exper. Med.
97. 711 (1953).
[68] B. H. Landing, A . Goldin, and H . A . Noe, Cancer2,1075 (1949).
[69] H. Jackson, Pharmacol. Rev. 11, 135 (1959).
[70] W. 0.Nelson, Fertil. Sterility 12, 109 (1961).
[71] H. Jackson, B. W. Fox, and A . W. Craig, J. Reprod. Fert. 2,
447 (1961).
[72] H. Harmsen, Arztl. Mittlg. 46, 145 (1961).
Ange w. Chem. internat. Edlt.
Vol. I !I 962) / No. I5
1731 W. 0. Nelson, Acta endocrinol., Suppl. 28,7 (1956).
[74] W. 0. Nelson and E. Steinberger, Fed. Proc. 12, 103 (1953).
[75] W. 0. Nelson and R . G . Bunge, J . Urology 77, 275 (1957).
[76] J. T . Prior and J. H . Ferguson, Cancer 3, 1063 (1950).
[77] S. J . Segal, cited by [56].
[78] H. E. P a d , M . F. Paul, F. Kopko, R . C . Bender, and G.
Everett, Endocrinology 53, 585 (1953).
[79] E. Steinberger, A. Boccabella, and W. 0.Nelson, cited by [56].
'79a] E. Sreinberger, J. Reprod. Fert. 3, 250 (1962).
1801 H. Barsoum, J. Pharmacol. 115, 319 (1955).
[Sl] A. D . Bergner, Cancer 3, 134 (1950).
[82] W. Fleischmann and G. E. CJl/yot, Cancer 3, 130 (1950).
[83] N . Kaufman, J. V. Klavins, and T. D . Kinney, Amer. J. Pathol.
32, 105 (1956).
543
testes
(spermatogenesis
and meiosis)
t bis (dichloroacetyl) diamine (B);
cellular poisons and mitotic inhibitors
(C); antimetabolites and Cd salts (D)
YI
epididymis
(sperm maturation)
t alkyl sulfates (e.g. Myleran) (D)
J.
vagina
t spermicidal agents (A)
I
V
tubes
(penetration of outer
layer of ovum)
+..-
sperm damage (inhibition of
penetration)
.1
fertilization
t---sperm damage (interference with
fertilization)
possibility of not only systematically blocking spermatogenesis but also of affecting the sperm depot [71].
With the single exception referred to, all methods designed to act systemically on sperm cells are characterized by the dangers of poor toleration or toxicity.
Vaginally applied spermicidal agents, on the other
hand, are safe, easily applied and relatively reliable (see
Table 4); hence they dominate the contraceptive market.
Applied as pastes, jellies, suppositories, foams or tablets
and inserted just at the mouth of the cervix, they act to
immobilize the sperm [115, 1161. Table 4 lists a number
Scheme 4. Contraception by selective action on the sperm cell.
A = tested in humans, commercially available
B = tested in humans, application possible
C = tested in humans, of uncertain promise or has undesirable
side effects
in animals, use in humans uncertain oc impossible
f --.- = suggested application
D
= tested
Sulfuric acid alkyl esters, depending on their chemical
structure [71], not only interfere with the early stages of
spermatogenesis,i. e. spermatogonia and spermatocytes,
but also act on the maturing sperm cells in the epididymis and the testes [85, 113, 1141. This opens up the
[84] I. Rosenfeld and 0. A. Bearh, Proc. SOC.exp. Biol. Med. 87,
295 (1954).
[85] W . Eollag, Schweiz. med. Wschr. 84, 393 (1954).
[86] M . C. Chang: Proceedings Sixth internat. Conf. Planned
Parenthood. London 1959, p. 129.
[87] C. W . Emmens: Proceedings Sixth internat. Conf. Planned
Parenthood. London 1959, p. 325.
[88] S. J. Segal, Eugenic Quarterly 6, 94 (1959).
[89] S. J. Segaland W . 0 . Nelson, Proc. SOC.exp. Biol. Med. 98.
431 (1958).
[90] S. J. Segal and A . Tyler, Biol. Bull. 115, 364 (1958).
[91] C. H . Danforrh and E. Carer, Proc. SOC.exp. Biol. Med. 86.
705 (1954).
[92] D . Haskin, Anatom. Rec. 102, 493 (1948).
[93] M . L. Murphy, D . A . Karnofsky, and J. Roddy, Proc. Amer.
Assoc. Cancer Res. I , 34 (1954).
[94] H. Jackson and M. Bock, Nature (London) 175, 1037 (1955).
[95] J. B. Thiersch, Acta endocrinol., Suppl. 28, 37 (1956).
[96] J . E . Thiersch, Proc. SOC.exp. Biol. Med. 94, 36 (1957).
[97] M . A . Sanders, B. P . Wiener, and J. Yudkin, Nature(London)
180, 1015 (1961).
I981 1. B. Thiersch, Proc. SOC.exp. Biol. Med. 98, 479 (1958).
[99] J. B. Thiersch in: Proc. Sixth internat. Conf. Planned
Parenthood. London 1959, p. 157.
[IOO] K . Didcock, D. Jackson, and J . M . Robson, Brit. J. Pharmacol. Chemotherapy 11, 437 (1958).
[I011M. G . Kelley and J. L. Hartwell, J. nat. Cancer Inst. 14, 967
(1954).
[lo21 A . Tyler in: Proc. Sixth internat. Conf. Planned Parenthood.
London 1959, p. 138.
[lo31 B. P . Wiesner, M . Wove, and J. Yudkin, Stud. Fertil. 9, 129
(1958).
[lo41 F. W. Sfamler, Proc. SOC.exp. Biol Med. 90, 294 (1955).
[lo51 D . Jackson and J. M . Robson, Brit. J. exp. Pathol. 39, 133
(1958).
[I061 J. E . Thiersch, Ann. N.Y. Acad. Sci. 60, 220 (1954).
[I071 J. B. Thiersch, Amer. J. Obstetr. Gynecol. 63, 1298 (1952).
[lo81 S. C. Hartmann, B. Levenberg, and J. M . Buchanan, J. biol.
Chemistry 221, 1057 (1956).
[lo91 M . L . Murphy and D . A. Karnofsky, Cancer 9, 954 (1956).
[I101 J. E. Thiersch, Proc. SOC.exp. Biol. Med. 94, 27 (1957).
[ 1 1 11 J. E. Thiersch, Proc. SOC.exp. Biol. Med. 94, 33 (1957).
[112] J. B. Thiersch, Proc. exp. Biol. Med. 97,888 (1958).
[113] A. W. Craig, E. W. Fox, and H . Jackson, Nature (London)
181, 353 (1958).
[114] H . Jackson, J. Faculty Radiologists 9, 217 (1958).
544
Table 4. Spermicidal materials to be applied vaginally
Material
Trade name
Manufacturer
Lactic and boric acids
Zontraceptalene
Lamberts Ltd.,
Dalstone, England
Boric acid, aluminum
acetotartrate,
formaldehyde, and
chlorocarvacrol
Patentex
Patentex GmbH.,
Frankfurt
Mercuric phenylacetate
and lactic acid
Prophylcols
Labopharma, Berlin
Boric acid, lactic acid,
methyl- and propyl-phydroxybenzoic acids,
hydroxycinchonine
Confidol
Pharmasal,
Hannover
Mercuric phenylacetate
Volpar, Mycon
British Drug Houses
Ltd., London Allied
Laboratories Ltd.,
London
Mercuric phenyldinaphthylmethanedisulfonate
Penotrane
Ward Blenkinsopp
and Co. Ltd.,
London
Castor oil and sodium
lauryl sulfate
Ortho Creme
Ortho Pharmacy
Ltd., High Wycombe,
Bucks., England
Castor oil and p-diisobutyl phenoxypolyetboxyethanol
Ortho Jelly
Ortho Pharmacy
Ltd.
Nonylphenoxypolyethoxyethanol, potassium ricinoleate, and sodium lauryl
sulfate
Staycept cream
Stayne Laboratories,
Ltd., Wakingham,
Bucks., England
Nonylphenoxypolyethoxyethanol and benzylethonium chloride
Emko Foam
Emko Co.,
St. Louis, USA
Hexylresorcinol
C. P. Ointment,
Jelly Prentif Gel
Gilmont Products,
London; Prentif Ltd
London
o-Hydroxyquinol sulfate
Semori
Luitpold-Werke,
Munich
Triisopropylphenoxypol yethoxyethanol
Vol Fam Creme
Aries Ltd.. London
Dioctyl sodium sulfosuccinate and paraformaldehyde
Antemin
Coates and Cooper
Ltd., London
Chloramine
Gynaniin
Coates and Cooper
Ltd., London
Chloramine and zinc
phenol sulfate
Bymeston
Lamberts Ltd.,
Dalstone, England
Zinc phenol sulfate
Rendell Foam
W. J. Rendell Ltd.
Cellulose sulfate
A-Gen
Dr. Herbrand,
Gengenbach/Baden,
Germany
11 151 J. MacLeud, A . Surbrero, and W. Inglis, J. Amer. med.
Asoc. 176, 421 (1961).
[I161 M . E. Paniagua, P . R . Rio Piedras, A. E. Vaillant, and C. J.
Gamble, J. Amer. med. Assoc. 177, 125 (1961).
Angew. Chem. internat. Edit. [ Val. 1 (1962) [ Ma. 10
of compounds that have been tested for spermicidal
effect and have also been tested extensively for how well
they are tolerated in the vagina. Under the stimrilus of
the Planned Parenthood Association, test methods for
spermicidal preparations were developed [116a-c] and
regular lists of useful preparations are published (Approved List of Contraceptives by the Family Planning
Association, London SW 1 ;last available edition: 1959).
Using these methods, the spermicidal activities of numerous compounds, mainly detergents [116d], were
tested in vitro.
Finally, it is conceivable to treat the maIe partner so as to
damage his sperm (without effecting any apparent morphological defects) in such a way as to prevent it from
penetrating the ovum and thus consummating fertilization.
So far this has not been observed. However, male sterility
caused by autoantibodies against sperm has been described
[116e]. Treatment of semen with artificially produced serum
antibodies prevented conception [116f].
9)
Ova (see Scheme 5)
It is considerably more difficult to affect either the unfertilized
or the fertilized ovum (see Scheme 5 and Table 3). So far no
entirely harmless procedure has been developed for humans,
ovary
(phase of follicle
maturation)
c Myleran, selenium (D)
+.-. mitotic inhibitors, antimetabolites
J
tubes
t MER-25 (D)
(maturation processes) t-.- mitotic inhibitors, antimetabolites
I
tubes
(fertilization)
J.
tubes and uterus
t cell poisons, mitotic inhibitors,
(development of trophoantimetabolites, Cd salts (D)
blast prior to nidation)
c
uterus
(development of embryo 4following nidation)
cell poisons (D)
Scheme 5. Prevention of pregnancy by selective action on the
ovum or the fertilized ovum.
Symbols as in Scheme 4
nor are such procedures known from animal experiments.
Myleran is the only compound with which it was possible to
demonstrate a n ovicidal action preceding ovulation 1851.
Selenium, added to the drinking water, appears to damage
the ovum to the point where fertilization can no longer take
place. Of interest is the action ascribed to MER.25, I+-2diethylaminoethoxyphenyl)-l-phenyl-2-p-anisylethanol;this
compound is said to change the outer layer of the ovum to
the point where sperm penetration is prevented [86].
y) Fertilized ovum (see Table 3)
Extensive studies are being carried out to test the possibility
of providing the mother with embryotoxic materials that are
harmless to her (selective embryotoxicity). These should be
applicable either before or after nidation. The danger exists,
[116aJ J . MacLeod, A. J. Sobrero, and W. Inglis, J. Amer. med.
Assoc. 176, 427 (1961).
[116b] W. N. Harris, J. Reprod. Fertility 3, 105 (1962).
[116c] CI. Harvey and R . E. Stuckey, J. Reprod. Fertility 3, 132
(1962).
[ I lad] CI. Harvey and R. E. Stuckey, J. Reprod. Fertility 3, 124
(1962). [116e] A. S . Parkes, J. Reprod. Fertility 3, 160 (1962).
[llaf] A. C. Menge, W . H . Stone, W. J . Tyler, and L. E. Casida,
Reprod. J. Fertility 3, 331 (1962).
Angew. Chem. internat. Edit. Vol. 1 (1962) 1 No. 10
however, that a n insufficient dose may result in the birth of a
live but malformed baby [*I. Hence such compounds seem
unsuitable for contraceptive purposes.
b) Materials that affect other physiological or biochemical processes concerned with conception
Numerous discussions and systematic investigations
have been concerned with the question whether or not
the fundamental physiological and biochemical processes Concerned with conception can be affected in such
a way as to inhibit conception. Practical results have
been obtained in either sex only by the use of compounds that act directly on the regulatory center.
In principal, two possibilities can be considered for use in
women: sustained morphine medication is known to cause a
reversible blocking of the hypothalamic sex regulatory center
[ 1171. In chickens and rats, this method has been applied with
success but has not been pursued further [118,119]. Similarly,
the antiovulatory effect of neuroplegic and sedative agents
observed in animal experiments has not been tested in
humans. It seems possible to develop a morphine analogue
that is not addictive and is also free of other side effects.
Another possibility is to simulate the central inhibition
of the periodicity of ovarian function by the use of
ovariogenic and placental steroids. Pincus et al. [1201221 have proved the applicability of gestagenic steroids
taken by mouth for this purpose. Functional and psychological considerations led to the combination of a gestagen with an estrogen, to be taken daily. When taken in
the prescribed cycle of 20 days on and 10 days off the
medication, this combination not only inhibits ovulation
but also induces a cyclelike growth and sloughing off of
the endometrium. Studies have shown that the drug does
not suppres the basic secretion of gonadotropin but
merely inhibits the rise in the blood level, which induces ovulation and which is normally part of the first
phase of the cycle 11231. On interrupting the treatment,
the normal cycle returns, and fertility reappears [124,
1251. Of the estrogen-gestagen combinations listed in
Table 5, Enovid@is the oldest.
Attempts at improving effectiveness, questions of tolerance, and price have led to the development of other
similar preparations, among which Anovlar seems to
be particularly well tolerated [124, 125, 170a-c]. After
treatment with ovulation-inhibiting steroid combina@
[*I This is the only possibility where the use of contraceptives
can give rise to malformations. Malformations due to the use
of other type of contraceptives have often been claimed, but such
claims have not so far been conclusively substantiated. However,
none of these methods seems applicable without affecting the
mother.
[I171 M . F. Meyer, Zbl. Gynakol. 60, 47 (1936).
[I181 G. Dorner and W . Hohfweg, Arch. Gynakol. 91,463 (1959).
[I191 G . Knappe and G . Downer, Zbl. Gynakol. 81, 2073 (1951).
[I201 G . Pincus, Acta endocrinol., Suppl. 28, 18 (1956).
[I211 G. Pincus, J. Rock, and C. R. Garcia, Amer. J. Obstetr.
Gynecol. 75, 1333 (1958).
(1221 G. Pincus, C. R . Garcia, and J . Rock, Science (Washington)
130, 81 (1959).
[I231 R. Buchholz, Lecture, Meeting of the Nordwestdtsch. Ges.
Gynakologie, Kiel, 1961.
[I241 F. Peeters, Lecture, Meeting of the Nordwestdtsch. Ges.
Cynakologie, Kiel, 1961.
[I251 F. Peeters, M . van Roy, and H . Oeyen, Med. Klin. 56, 1679
(1961).
545
Table 5. Contraceptives that act on other processes that are necessary for conception (for symbols see caption of Scheme 4)
Supposed or proven mode of action
Material
Category
In the male
Ref.
Catewry
In the female
Ref.
Steroid hormones
Ethynyl- 19-nortestosterone acetate
(Primolut (N)" Schering)
A
1701
Ethynyl-l9-nortestosteroneand ethynylestradiol (Anovlar", Schering)
A
1124,1251
Ethyl-19-nortestosterone
(Nilevar", Searle)
B
[701
Ethynyl- A% 10- 19-nortestosterone and
ethynylestradiol-3-methyl ether
(Enovid@,Enavid", Conovid"; Searle)
A
[70,122,133]
Ethynyl- 19-nortestosterone and ethynylestradiol-fntethyl ether (Orthonovum;
Ortho)
A
Ethynyl-A4-estren-17-01 (ethynyl-3-deoxo19-nortestosterone) and ethynylestradiol-3methyl ether (Lyndiol; Organon)
A
6x-Methyl-l7-hydroxyprogesterone acetate
and ethynylestradiol (Protex; Leo)
A
Testosterone
B
inhibits spermatogenesis
B
Estrogens (steroids or stilbenes)
C, D
inhibit spermatogenesis
B
D
Gestagens (19-norprogesterone, gestagens)
B
D
inhibit spermatogenesis
D
19-Norgestagens
-
inhibit ovulation by action
on diencephalon
I1 341
[127,136.1371
in small doses they
accelerate transport of the
ovum through the tubes,
thereby preventing nidation;
in large doses they block
transport through the tubes
and thus prevent nidation
prevent nidation by acting
on endometrium
act on cervical mucus
(preventing the passage of
the sperm); inhibit
nidation in endometrium
[ 144- 1481
[77,14-150]
Antihormones
Antigonadotropines
D
inhibit spermatogenesis
induce hypotrophy of ovaries
and genital tract
Pituitary inhibitors (nonsteroids)
Dithiocarbamoyl hydrazines (particularly
1-methylallylthiocarbamoyl-2-methylthiocarbamorlhydrazine)
chemical blocking of
gonadotropin releasers or of
gonadotropin production
MER-25
decreases secretion in the
tubes
Anti-inflammafory agents
Antihistaminics
Monoaminooxidase inhibitors
D
diminish male fertility
(sperm damage?)
5-Hydroxytryptamine
[132al
D
D
inhibit nidation by
diminishing the effect of
estrogens and gestagens
D
D
ditto and estrus inhibition
kills fetus in 2nd half of
pregnancy
C, D
C
prevents fertilization
inhibits ovulation
1691
t5.1521
[153,1541
[153,1551
So-called hyaluronidase inhibitors
Hesperidine phosphate
Cirantin (pyrone derivative)
11021
[ 156,1571
Neuroplegic materials and sedatives
Reserpine
Chloropromazine
Morphine
[I261 M. Apostolakis, Acta Endocrinol. 37, 75 (1961).
[1271 S. A. Geist, J. A . Gaines, and U.D . Salmon, Proc. SOC. exP.
Biol. Med. 44, 319 (1940).
[1281 H. Selye and S. Friedman, Endocrinology 28, 129 (1941).
546
D
D
C, D
inhibit ovulation by acting
on diencephalon
[158,1591
[I601
[1l7-1191
[I291 W. 0. Maddock, R . B. Leach, I . Tokuyama, C . A . Paulsen,
W. 0. Nelson, E. C. Jungck, and C. G. Heller, Acta endcrinol.,
suppi. 28, 55 (1956); A. Tyler, J. Reprod. Fert. 2,473 (1961).
[I301 N. J . Heckel and J. H . MacDonald, Fertil. Sterility 3, 49
(1952).
Angew. Chem. internat. Edit.
Vol. 1 (1962) No. 10
Continuation Table 5
1
Material
Supposed or proven mode of action
Ref.
1 z!: 1
I
I l
D
--
Plant hormones
-I
Ergotoxins (active components:
ergocornin and ergocryptin)
m-X ylohydroquinone
Embelia ribes, Piper Iongum
and asdetida
[131]N. J. Heckel, W. A. Rosso, andL. Kestel, I. clin. Endocrinol.
11, 235 (1951).
[132]D. J. Ludwig, Endocrinology 46,453 (1950).
[132a]J. W. Rowlands, Proc. Roy. SOC.(London), Ser. B. 121,
517 (1937).
[132b]H.Tuchmann-Duplessis and L. Mercies Parof, C. r: hebd.
S6ances Acad. Sci. 235,712 (1961).
[I331E. Mears, Brit. med. J. No. 5261, 1179 (1961).
[134]J. W. Goldzieher, L. E. Moses, and L. T. Ellis, Millbank
Mem. Fund Quarterly (1960).
[135]R. Kaiser, Geburtshilfe, Frauenheilkunde 22, 122 (1962).
[136]A. A. Loeser, Lancet I , 373 (1938).
[137]G. N. Papanicolaou, H. S. Ripley, and E. Shorr, Proc. SOC.
exp. Biol. Med. 37,689 (1938).
11381 C.R.Austin and H. M . Bruce, J. Endocrinology 13,376(1956).
[139]H. 0.Burdick, R. Whitney, and G. Pincus, Anatom. Rec. 67,
513 (1937).
[140]R. Whitney and H. 0.Burdick, Endocrinology22,639(1937).
[I411 H. 0.Burdick and G. Pincus, Amer. J. Physiol. I I I , 201
(1935).
[142]H. 0.Burdick and R. Whifney,Endocrinology 21,637(1937).
[143]R. Whitney and H.O.Burdick,Endocrinology 20,643 (19.36).
[144]G. Pincus and R. E. Kirsch, cited by [56].
[145]C. W. Emmens, cited by [561.
[I461 C. W. Emmens, R. I. Cox, and L. Martin, J. Endocrinology
18, 372 (1959).
[I471A. S. Parkes, E. C. Dodds, and R. L. Noble, Brit. med. J. 2,
557 (1938).
[I481J. Velardo, N. M. Raney, B. G. Smith, and S. H. Sturgis,
Fertil. Sterility 7, 301 (1956).
(1491R. L. Cochrane and R . K. Meyer, Proc. SOC.exp. Biol. Med.
96, 155 (1957).
[150]F.L. Hisaw, J. T. Velardo, and X. K. Ziel, J . clin. Endocrinol. 14, 763 (1954).
[150a]G. Bourdel, Gen. compl Endocrinol. 1, 375 (1961).
[151] G. E. Pager, A . L. Walpole, and D. N. Richardson, Nature
(London) 192, 1191 (1961).
Angew. Chem. internat. Edit./ Vol. 1 (1962)1 No. 10
1
D
D
D
c, D
[l6Obl
[160hl
toxic to embryo
after nidation
inhibit nidation,
toxic to embryo
I
C, D
[160a, b]
inhibit nidation by
stimulating unphysiological
mobility of the genital tract
I/
D
Indolyl-3-acetic acid
Plants and plant materials
Lith >spermurnruderale,
Lithospermum officinale
Lycopus virginale
Pulygonum hydropiper L.
1
--
Contact insecticides
Thiophosphonic ester 1E 6251
Hexachlorocyclohexane
Ref.
--
Syrnpaticolyf ics
Ergot alkaloids (Neo-gynergen)
1
1
:I
Parmymparicomirnetics
Pilocarpin
Physostiguin
In the female
1
I
i)
[160bl
1
inactivate gonadotropins
inhibits gonadotropins in
anterior pituitary
prevent nidation by
inhibiting gestagens
estrogen and progesterone
antagonist
[161,1621
11631
[162,164]
1165,1661
170,120,
167-1701
peripheral gonadotropin
inhibition
[70,1671
block estrogen-induced
[1721
enzyme activation
[ M a ] L. Masrroianni, R. AbduCKarim, U. Shah, and Sh. J.
Segal, Endocrinology 69, 396 (1961).
[152]M. E. Shelesnyuk, Endocrinology 54, 396 (1954).
[153]E. Poulson, M. Botros, and M. Robson, Science (Washington) 131, 1101 (1960).
[154]W. G. Spector, J. Reprod. Fertility 2,362(1961).
[155]J. M.Robson, E. Poulson, and 1). Lindsay, J. Reprod. Fert.
2, 530 (1961).
I1561 G. Schubert and F. X. Wohlzogen, Wien. med. Wschr. 109,
267 (1959).
[157]F.X. Wohlzogen, Acta Endocrin. 37,298 (1961).
[158]V.L. DcFeo and S. R. M . Reynolds, Science (Washington)
124, 726 (1956).
[l59]R. L. Meier: Modern Science and the Human Fertility
Problem. Wiley, New York 1959.
[I601 C. A . Barraelough, Anatom. Rec. 124, 255 (1956).
[16Oa]E. Schilling, Z. Tierziicht. Ziichtungsbiol. 60,263 (1952).
[160b]M. Dallmann, 2.Tierziicht. Ziichtungsbiol. 65,46(1955).
[I611Fr. KernHr, Armeimittelforsch. 9, 368 (1959).
[162]R. L. Noble in: Proc. Sixth internat. Conf. Planned Parenthood. London 1959, p. 243.
I1631 F.Kemper and A. Loesner, Acta endocrinof. 38,200(1961).
[164]J. Eust, J. Endocrinology 12, 252 (1955).
[165]M. C. SheZesnyak, Acta endocrinol., Suppl. 28, 106 (1956).
[I661 R. A. Carlsen, G. H. Zeilmker, and M. C. Shelesnyak, J.
Reprod. Fert. 2, 369 (1961).
11671 S.N.Sanyal in: Proc. Sixth internat. Conf. Planned Parenthood. London 1959, p. 254.
[168]S.N. Sanyal and S. Ghosh, Acta endocrinol., Suppl. 28,83
(1 956).
[169]K. B. Baira and S. Hakim, J. Endocrinology 14,228 (1956).
[170]J. B. Thiersch, Acta endocrinol., Suppl. 28,46 (1956).
[170a]J. Huller, Geburtsh., Frauenheilk. 22, 211 (1962).
[170b]G.J.M. Swyer, Medizin.Mittei1. (ScheringAG.)23,3 (1962).
[17Oc] E. Mears, Lecture, Annual Conference SOC. Study of
Fertility, London 1962.
[170d]Brit. med. J. 53, 315 (1962).
547
tions, thromboses were observed in some cases who had
previously suffered from thrombophlebitis and/or
thromboembolism. There is, however, no direct connection between medication and thrombosis [170 d]. Nevertheless, these cases are not ignored: preparations of the
kind mentioned should not be given to women with a
tendency to develop thrombosis.
In males, too, orally administered gestagens can inhibit
sperm cell maturation by blocking the central regulatory
control [126]. Of interest is the suppression of libido in
males in the course of medication, whereas this is not
true in women.
Both estrogens and androgens block the hypothalamic
regulatory center in men and women, but their side effects
are such as to prohibit administration of the necessary doses
[127,128].
Inaddition to methodsaffectingthe diencephalon region,
it is also conceivable to inhibit the initial stages of the
regulatory cycles in both sexes by means of antigonadotropins and by blocking the anterior pituitary by antireleasing agents (see Schemes 6 and 7 and also Table 5).
hypothalamus (sex
t gestagens and androgens (B);
estrogens (C)
center in diencephalon)
5
gonadotropin releaser
J.
anterior pituitary
1
gonadotropins (FSH,
ICSH)
5
testes
4
epididymis
.1
secondary sex glands
(prostate, seminal
vesicles)
f ---
antireteaser hormone
t Polygonum hydropiper (D)
t chemical block of gonadotropin
production (D)
t m-xylohydroquinone (C)
+.-.- antihormones; Lithospermum species
t estrogens (D)
f.-.
monoaminooxidase inhibitors (D)
f..effect on antigaglutininformation
and sperm maturation
t-- effect on agglutinin or antiagglutinin
formation; inducers for transforming
sperm metabolism to aerobic
Scheme 6. Prevention of pregnancy by interfering with processes
in the male that are essential for conception.
For symbols see caption of Scheme 4
hypothalamus
(sex center in diencephalon)
4
gonadotropin releaser
t gestagens (A); androgens and
estrogens (B); morphine (C);
neuroplegic psychic inhibition(D)
f
antireleaser hormone
J.
anterior pituitary
-1
gonadotropins (FSH, ICSH,
LTH)
t Polygonum hydropiper
t chemical blocking of gonadotropin production (D)
t Lithospermum species, antihormones (C); Lycopus virginale (D)
5
ovary (follicle maturation and
ovulation)
6-
hyaluronidase inhibitors, monoamine oxidare inhibitors (D)
5
tubes (transport of ovum and C m-xylohydroquinone(C); estrosperm, milieu of fertilization)
gens (D)
+.-. effect on antiagglutinin formation
or anaerobic metabolism or
motility (D)
uterus (preparation for
t m-xylohydroquinone (C);gestagens, estrogens, antihistaminic
nidation and nidation)
agents, antiinflammatory agents,
ergotoxins (D)
+...- induction of sperm antibodies and
antibodies to gestagsn proteins
t gestagens ( C )
cervix
(sperm penetration)
I
J.
I
1
Schema I. Prevention of pregnancy by interfering with processes
in the female that are essential for conception.
For Symbols, see caption of Scheme 4
548
Observations have been made in humans on the transitory accumulation of antigonadotropin and the resulting
inactivation of gonadotropin [129]. However, major
difficulties oppose the widespread use of these antihormones.
Greater success seemed possible with plant derivatives which
apparently act as gonadotropin inactivators by way of a
pituitary block. On the basis of popular officinal medicine,
Polygonum hydropiper, Lithospermum species, Lycopus virginicus and Pisum sativum have been studied intensively. A
stable and defined product was obtained only from the pea
plant, viz. m-xylohydroquinone [70,167,168,171]. Widespread
clinical trials notwithstanding, its contraceptive qualities
have not been definitely established, and the claim for its
mechanism of action remains unproven. Preparations made
from other than the above mentioned plants have been
tested with positive results in animal experiments and, in
some instances, clinically [lal]. Until now they have proved
impractical because they lack stability and are tolerated
oorly, and because it is difficult to obtain enough starting
material [162,163].
There has been some discussion concerning the use of sperm
agglutinins. An increased agglutinin titer might render the
sperm incapable of fertilization. No work has been done as
yet concerning the possible effect of changes in epididymal
metabolism on sperm maturation with the aim of rendering
the sperm sterife. Such a procedure would not exclude the
possibility of malformations.
In the female more succes is likely to be achieved by interrupting the regular cycle in order to prevent conception: thus in regulatory cycle I (see Scheme 1) inhibitors
of monoaminooxidase and hyaluronidase have been
shown in animal experiments to prevent the rupture of
the follicles induced by ICSH. The ovum dies and the
follicle either atrophies or luteinizes [156,157].
In the case of regulatory cycle I1 (see Scheme 2) it has
been shown in animal experiments - and quite possibly
only because of species-specific mechanisms - that
small doses of estrogens accelerate the movement of the
ovum through the follicles and thereby inhibit fertilization or nidation. Large doses of estrogens under similar circumstances block movement of the ovum h the
oviduct; this causes the arrival of the fertilized ovum to
be out of phase with nidation. Thus nidation can be prevented by interference with the physiological relationship between estrogens and gestagens.
Function of the corpus luteum, fertilization, and nidation
are so delicately adjusted in time that interference with
on8 of these factors makes it impossible for nidation of
the fertilized ovum to occur. It might be possible to do
in humans what has been done in dogs, i.e. to inject
estrogens just after copulation. However, this would
require the injection to be given within a few days after
conception had occurred. Moreover, diagnosis of pregnancy can be made only at a time when steroids can no
longer affect nidation.
If done at the right moment, nidation can also be prevented by the administration of anti-inilammatory substances (Table 5 and Scheme 7). Apparently these compounds block the development of the decidua in the
endometrium as induced by estrogens and gestagens;
this development closely resembles an acute inflammation [5].
[I711 S. N. Sanyal, Acta endocrinol., Suppl. 28, 72 (1956)
Angew. Chem. internut. Edit. 1 Vo1. I (1962)/ No. 10
A combination of plant materials, discussed in ancient
Indian medical literature, blocks the estrogen-induced
increase in enzyme activity [172]. Experiments with mice
have shown that nidation can also be prevented by upsetting the endocrine equilibrium needed for this process [173]. Induction of unphysiological motility of the
genital tract before nidation has occurred greatly decreases the viability of the embryo (cf. Table 5).
The question remains whether the anaerobic metabolism
which prevails at the beginning of the second regulatory cycle
and which provides an optimum milieu for fertilization can
be affected in any way. This in turn would modify some of the
functions in the female genital tract needed to effect conception; for example, the production of antiagglutinins and“fertilisins” needed for capacitation of the sperm might be affected.
It has been possible to produce an antigen from sperm
and also antiserum against spermatozoa of different
species [174].
It is not yet possible to foretell the practical significance
of the many measures discussed in this article. As yet
there is competition on the one hand between contraceptive measures that interfere with certain of the mechanisms of conception and mechanical devices, and, on
the other, between these and attempts t o determine the
nonfertile period in the second regulatory cycle (e.g. by
means of the Knaus and Ogino calendar, by measuring
the vaginal temperature in the morning in order to determine the postovulatory rise in temperature caused by
progesterone, or by pregnanediol determination according to Reimann - Hunziker and Wild [175]). On
the basis of statistics, it can be asserted that, when
properly used, gestagens that inhibit the sex center and thereby prevent ovulation have the greatest
contraceptive potentialities and reliability (practically
100 %).
Received, January 24th. 1962 [A 225/47 IE]
[I721 H . S. Chakravarti, J. Indian med. Assoc. 37,322 (1961).
11731 H. M . Bruce, J. Reprod. Fertility 2, 138 (1961).
[I741 A . S.Parkes, J. Reprod. Fertility 3, 158 (1962).
[I751 R . Reimann-Hunziker and W Wild,Med. Klinik 57, 440
(1962).
COMMUNICATIONS
Anionic Heterosiloxanes [ l l
By Dr. H. Schmidbaur and Prof. Dr. Max Schmidt
Institut fiir Anorganische Chemie
der Universitat Marburg/Lahn (Germany)
The siloxyl groups forming coordination bridges between
two metal atoms in the dimeric tris-trimethylsiloxy compounds (I) of Al and Ga [2] account for the great readiness
with which these compounds add on metal siloxides (11).
Even at room temperature, equimolar mixtures of solutions
of { [(CH3)3SiOl3A1}2 or { [(CH3)3SiO]3Ga)z and NaOSi(CH&
or KOSi(CH3)3 in CC4 yield white precipitates of the
sodium or potassium tetrakis-trimethylsiloxy-alanates (111)
or -gallanates (IV) in an exothermic reaction, e.g.
SiR,
RsSi
I
‘o\AI/o\A,/o
/ \o/ \o
RaSi/ O
S~R,
I
PR3
+ 2 R,SiOeM@ 4
'Sib
(11)
(1)
(M = Na or K ; R = CH3). These sodium and potassium salts
are insoluble in organic solvents, and begin to decompose
slowly at temperatures above 250 “C. Their infrared spectra
in Nujol show bands, whose positions prove the existence of
discrete anions (v Si-0-A1 at 10.35 p and v Si-0-Ga at
10.80 p). Analogously prepared lithium salts are soluble in
organic solvents, are fusible, sublime in vacuo, and have
infrared spectra unlike those of the Na and K salts. The
spectra of the Li compounds indicate a strong homopolar
linkage of the metal to the anion, as well as the presence
of molecular association, which is further confirmed by
molecular weight determinations. The proton magnetic
Angew. Chem. internat. Edit. / Vol. I (1962)/ No. 10
resonance spectra in CC4 show only one sharp resonance
singlet, which is an impressive proof of the equivalence of all four siloxyl groups (chemical shift for
Li(Al[OSi(CH3)3]4),-0.125 ppm; for Li(Ga[OSi(CH&I4),
-0.165 ppm [3].
The anions of 111 and IV are isosteric with the neutral siloxanes Si[OSi(CH3)3]4 and Ge[OSi(CH3)314, for example:
R3Si
/SIR3
‘0
\cia/’
\o
- R3Si/O
‘SiR3
(JW
I‘
R3Si
PiR3
O
\
and
\Ge/O
/
R3Si/ O
\o
‘SiR,
B.p. 59-6O0C/1 mm.; m.p. -59°C [41
Their infrared and proton magnetic resonance spectra show
the complete structural identity of the tetrahedral ionic and
neutral siloxane compounds. With analogous “complex
silicones”, where iron was the heteroatom, we obtained
similar results [l].
Received, June 22nd. 1962
[Z 305/139 IE]
[I] Heterosiloxanes,Communication X.-Communication IX : H.
Schmidbaur and M . Schmidt, J. Amer. chem. SOC.,in press.
[2J H. Schmidbaur and M . Schmidt, Angew. Chem. internat.
Edit. I, 328 (1962).
[3] Varian A 60 (60 Mc); solutions of all substances in CC14 at
c = 5 i 1%, with tetramethylsilaneas internal standard.
[4] First prepared by us from GeC14 and four moles of
NaOSi(CH3)s in anhydrous ether.
Bis(tripheny1phosphe)-ethylene-nickel
and Analogous Complexes
By Priv.-Doz. Dr. G. Wilke and Dip1.-Chem. G. Herrmann
Max-Planck-Institut fur Kohlenforschung
Mulheim/Ruhr (Germany)
By the interaction, at approx. 20 “C,of nickel acetylacetonate
with (CzH&AIOC2Hs in the presence of triphenylphosphine
(TPP) (Ni: P = 1 :2) in benzene, bis(tripheny1phosphine)ethylene-nickel, (TPP)ZNi.C2H4) is produced in yellow
549
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