Sex hormones and thyroid hormones

Thyroid Factor

The Natural Thyroid Diet

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I Sex hormones

(a) Female sex hormones

Oestrogens are the hormones concerned with the maturation of the female genital tract, the development of the secondary sexual characteristics and bone formation. The main oestrogens, oestradiol and oestrone, are secreted by the theca interna and appear in the fluid of the Graafian Follicles. Oestrogens are also secreted by the placenta and to a much lesser degree by the adrenal cortex. They are rapidly metabolized in the liver.

Progesterone is the hormone concerned with the maintenance of pregnancy. It is secreted by the corpus luteum and acts only on tissues formerly sensitized by oestrogens. It inhibits ovulation during pregnancy, depresses the action of oestrogens and produces further development of the breasts. It also plays a role in the development of the placenta and depresses uterine contractility.

The production of steroid hormones is controlled by the pituitary gonadotrophins (follicle-stimulating and luteinizing hormones). In large doses oestrogens can depress the gonadotrophs and lactogenic activities of the anterior pituitary gland. Because of their rapid metabolism by the liver, oral administration of the natural oestrogens is less effective than parenteral administration, with the possible exception of oestriol, which is claimed to be as potent when given orally as when given by injection.

The oestrogens are used to treat menopausal disturbances and cases of dysmenor-rhoea and menorrhagia. Progesterone is used chiefly in the treatment of functional uterine haemorrhagia. Both oestrogens and progesterone are used in the contraceptive pill.

Plants with oestrogenic constituents

The first plant constituents capable of replacing oestrone in hormone deficiency were found to be chemically identical with the animal hormone and were reported as early as 1933 (Butenandt and Jacobi, 1933; Skarzynski, 1933). It was, however, not until thirty years later that the oestrogenic substances in plants were investigated further. A review of the steroid oestrogens in higher plants was published by Heftman in 1967.

Other plant substances, although chemically not identical to them, were subsequently found to be able to replace the biological functions of the hormones (Shutt, 1976). Bennets and his coworkers (1951) noted the infertility observed in sheep which grazed exclusively on clover for a certain length of time in Australia. A compound isolated from clover was found to be oestrogenic (Biggers and Curnow, 1954) and was identified as genisteine, an isoflavine. Failure of sperm transport was later found to be the cause of the infertility of the ewes (Lightfoot et al., 1967). Subsequently, other isoflavones with oestrogenic activity were found in forage and other plants (Shutt, 1976; Adams, 1977; Livingstone, 1978). Also reported to be present in plants was another group of chemical compounds, the coumestans (skeletal structure 6H benzofuran 3-2-c-benzopyran-6-one), which have a higher oestrogenic activity than the isoflavones. A striking similarity of the skeletal structures of the isoflavones and coumestans with that of the synthetic oestrogen stilboestrol was noted by Farnsworth et al. (1975b). Of the constituents tested by these authors, the natural steroid oestrogens were found to be the most active, followed by the coumestans and then the isoflavones. It was further shown that daidzin (in Pueraria thunbergiana (Sieb. & Zucc.) Benth.) was the most active isoflavonoid derivative in the mouse uterine weight assay. Biochanin (in Dalbergia sissoo and spp. and in Lupinus tassilicus Maire) and genisteine (in TrifoKum baccarini Chiov.) were of lesser but approximately equal activity (Farnsworth et al., 1975a).

In search of plants with fertility regulating action, Farnsworth etal. (1975b) have listed the plants containing oestrone and oestriol. Some of these are found in West Africa: the date palm Phoenix dactylifera; the oil palm Elaeis guineensis; rice, Oryza sativa L.; wheat, Triticum aestivum L. and vegetable beans, Phaeseolus vulgaris L.

Phoenix dactylifera L. PALMAE

In Northern Nigeria dates, together with bran and the seeds of Sterculia tomentosa, are given to young heifers long before they are mature in order to cause them to become prolific breeders (Dalziel, 1937, p. 509). The pollen grains of the date palm, which is dioecious, are reported to act like gonadotrophins (El Ridi, 1960). Oestrone has been reported to be present in the kernels (Hassan and El Waffa, 1947; Heftman et al., 1966; Paris and Moyse, 1967, Vol. II, p. 10), which also contain 5% protides and 8% lipids.

Elaeis guineensis Jacq. PALMAE

Disparity in results obtained by different investigators when analysing palm kernels for oestrone content can be explained by the fact that different varieties of oil palm produce fruits with a varying thickness of mesocarp and size of kernel and extremes of being shell-less and kernel-less. The oestrone content of certain varieties could be confirmed (Butenandt and Jacobi, 1933; Bradbury and White, 1951).

Triticum aestivum L. syn. (Triticum sativum Lam. (wheat) GRAMINEAE

Oryza sativa L. (rice)

The seeds of these and other cereals mainly contain starches but the embryo (germ) at the base of the grain contains 10-20% lipids compared to the 1-2% in the albumen. The lipid fraction contains the sterols and the tocopherols (vitamin E). Thus wheatgerm-oil contains 85% of glycerides of non-saturated fatty acids, sterols and vitamins (mainly vitamin E). The oil is administered in cases of sterility in women and is also used in veterinary medicine in epizootic abortions.

It is interesting to note that vitamin E (a-tocopherol mainly) is found in the germs of cereals and also in different oils (palm oil, castor-oil (1%) and olive oil (Langlois, 1941)) and that deficiency of tocopherols is characterized by gestation troubles in females and testicular modifications in males (vitamin E is known to be a fertility factor (Bacharach, 1940)). Oryza sativa c. and Avena sativa c., both containing oestrone (Farnsworth et al., 1975b), have been shown to induce ovulation (Heftman, 1967; Paris and Moyse, 1967, Vol. II, p. 26).

Phaseolus vulgaris L. FABACEAE

The vegetable bean, also cultivated in some parts of West Africa, contains oestrone, oestriol and 17a-oestradiol (Kopcewicz, 1971). It contains more proteins (20-25%) than the cereals (8-15%) and only 1-7% lipids, including sterols and vitamin E, but has 61.6% glucides (Paris and Moyse, 1971, Vol. Ill, p. 201).

Arachis hypogeae L. FABACEAE

Another very important food plant, the groundnut, already mentioned in Chapter 2 (CV) contains an oestrogenic factor and a goitrogenic compound. The plant is treated in more detail below under Thyroid hormones.

Groundnuts contain an average of 42.8% of lipids and 26.2% of proteins and small quantities of vitamins, including vitamin E (Adrian and Jacquot, 1968).

Medicago sativa L. FABACEAE

Also cultivated as a food plant, M. sativa contains coumestrol and is rich in vitamins; mainly vitamin E is reported (Paris and Moyse, 1971, Vol. Ill, p. 391). Vitamin E is considered to be an antisterility factor (Bacharach, 1940). The activity of these oestrogenic food plants seems to be mostly concentrated in the germs and kernels. Other sources of oestrogens in West Africa might be the following plants.

Cyperus rotundus L. CYPERACEAE

The essential oil from the tubers shows oestrogenic activity. Fractionation of the oil produces an active hydrocarbon, cyperene I, which has a slightly less potent oestrogenic action than the oil and which also has an antispasmodic action on the uterus (Indira et al., 1956a, b; Abu-Mustafa el al., 1960) (see also Anti-inflammatory plants (Chapter 5)).

Holarrhena floribunda (Don.) Dur. & Schinz. APOCYNACEAE

A root decoction of Holarrhena is prescribed for sterility (Kerharo and Adam, 1974). The roots contain many steroid alkaloids. One of these, holophyllamine has significant oestrogenic activity (see more details under Plants acting like hormones of the adrenal cortex (Chapter 5)).

Funtumia africana (Benth.) Stapf APOCYNACEAE

The main alkaloid of the leaves, funtumine, is a 3a derivative of allopregnane with a ketone function at C-20. It is suggested that it might be of use in the hemisynthesis of hormones. Funtumine itself antagonizes the effects of oestrogens (see under Plants acting like hormones of the adrenal cortex (Chapter 5)).

It is only in the last few years that pharmacological and clinical details of the phyto-oestrogens have been mentioned. Most of the scientific data have been obtained in connection with the development of new methods of fertility regulation (Farnsworth et al., 1975a, b, 1983; Farnsworth and Waller, 1982). This application of the sex hormones currently represents by far the biggest practical demand. I have limited the other applications of the hormones to a few examples only.

Phytoandrogens are hardly mentioned in the literature. An androgenic steroid with an anabolic action in the healing of fractures has been found in Cissus quadrangularis (see Chapter 3).

(b) Plants in birth control

In order to be able to decide which of the very many species of plants should be tested for their effectiveness in birth control it has been necessary to consider the mechanisms by which the constituents exert their effect and to classify them according to the anatomical sites involved. This has greatly contributed to a better understanding of the plant oestrogens. Farnsworth et al. (1975a, b) have therefore enumerated the different antifertility mechanisms in laboratory animals. These are described briefly below.

The oestrogens are of interest in studies on fertility regulation because they can act as contraceptives by inhibiting the mid-cycle surge of pituitary gonadotrophin that is associated with ovulation.

Antifertility mechanisms

The organs on which antifertility agents may act in females are the hypothalamus, the anterior pituitary, the ovary, the oviduct, the uterus and the vagina. An antifertility agent can be classified by its action on each of these organs.

The pituitary. The functioning of this organ is under the close control of the hypothalamus via the follicle-stimulating and luteinizing-hormone releasing factors

(Goodman and Gilman, 1980, pp. 1389-92). Therefore, antifertility action at this level should include: (a) disruption of the normal hormonal functions of the hypothalamus and/or pituitary, e.g. by oestrogenic steroids and (b) interruption of the neural pathways to the hypothalamus that control the liberation of gonado-trophin-releasing factors.

Since the hypothalamus receives contributions from other areas of the brain, substances having CNS depressant activity and/or effects on neuro-hormonal transmission could be expected to alter gonadotrophin transmission. And indeed pentobarbital, morphine, atropine, tranquillizers (reserpine), anaesthetics and adrenergic (as well as cholinergic) blocking agents have been shown to block the ovulatory surge of luteinizing hormone in laboratory animals by having inhibitory effects on the hypothalamus (Smith, 1963).

Studies on laboratory animals such as the rat, mouse, hamster and guinea pig provide much information but the reproductive cycles of these animals exhibit species-specific differences as do those of men and primates, and different results with a given compound are often obtained.

Interference with gonadotrophin secretion may have post-ovulatory antifertility effects, but the antifertility usefulness of drugs having such effects is questionable not only because they have other pharmacological actions but also because animals (e.g. rats) sometimes become coitus-induced ovulators following blockade of their gonadotrophin surge (Farnsworth et al., 1975a).

In the guinea pig the pituitary can be removed after the third day of gestation without affecting the pregnancy and hypophysectomized women induced to ovulate by consecutive administration of follicle-stimulating hormone and human chorionic gonadotrophin have become pregnant without further gonadotrophin replacement therapy (Farnsworth etal., 1975a).

The ovary. Substances having antifertility properties may exert their effects at the ovarian level by inhibiting ovulation and/or steroidogenesis. Oestrogen administration early in the luteal phase has been shown, in monkeys and women, to decrease progesterone secretion and to hasten the onset of menstruation (Knobil, 1973). The lowering of post-ovulatory plasma progesterone levels may be at least one mechanism by which post-coitally administered high doses of oestrogen exert their antifertility effect in women.

The oviduct. Since successful implantation depends on the correct timing in the menstrual cycle of the arrival of the blastocyst in the uterus, disturbances of tubal transport may be accompanied by failure of implantation. Accelerated transport of ova results in a reduction in fertility, either through expulsion of the fertilized ova from the reproductive tract or through degeneration of fertilized ova that arrive (too early) in the non-receptive uterus. Either oestrogenic or anti-oestrogenic compounds may play a role in this inhibition. Anti-oestrogenic compounds are compounds which inhibit the effects of standard oestrogens such as oestrone, oestriol and oestradiol. Androgens and progestogens may show this activity and the weak plant oestrogens coumestrol and genisteine have also been shown to have this inhibitory effect (Folman and Pope, 1966). The anti-oestrogenicity of a compound can be demonstrated by the blocking of a step in the reproductive cycle that requires oestrogen.

The uterus. Antifertility agents that prevent ovulation and/or fertilization are called contraceptive agents whilst those that act after implantation has taken place are usually called abortifacients. The term 'interceptives' refers to compounds that act after fertilization has occurred to prevent implantation from taking place. Their earlier or later administration might render some of them contraceptive or aborti-facient, respectively.

Inhibition of implantation has been observed with a number of compounds and it appears possible that non-physiological treatment of the endometrium may impair fertility in the human. It has been suggested that an excess amount of oestrogen present in the uterus shortly after ovulation (in mammals) may prematurely sensitize the uterus so that the latter is in a non-receptive state at the time of arrival of the blastocyst. Other substances, instilled locally in the uterus, can impair fertility by affecting the endometrium or by causing physical obstruction of the lumen.

An abortifacient type of antifertility effect can be produced by compounds that stimulate uterine contractility. The hormone oxytocin can be used close to term to induce labour but is effective as an abortifacient if used earlier in a pregnancy. Prostaglandins, however, are now being widely used for the latter purpose. They appear to promote myometrial contractility, acting on both contraction and stretching of the myometrial wall. This produces a decrease in the levels of oestradiol and progesterone and the resulting endogenous stimulatory mechanism may be sufficient to complete abortion. If it is not, additional prostaglandin or oxytocin may be used.

Cervix or vagina. Antifertility activity exerted at the level of the cervix or the vagina can be based on the production of a cervical mucus that is 'hostile' to sperm penetration. Some of the spermicidal preparations are based on a trypsin-like protease (acrosin). Oestrogenic compounds produce vaginal keratinization (Farnsworth et al., 1975a).

Anovulation has also been observed in a number of cases as a result of inhibition of hypothalamic-hypophysial function, for example in Rhesus monkeys treated with reserpine (from Rauvolfia vomitoria) (Bianchi, 1962). But, as mentioned earlier, the suitability of using plants that act in this non-specific way is questionable because of the many different hormones that are controlled by this axis, for example the gonadotrophins (oestrogenic, luteinizing, prolactin, androgenic), thyrotrophin, and corticotrophin, and the changes in target organ function that result from effects on these hormones.

It has been reported that contraceptive steroids produce changes in metabolic processes, for example deterioration in glucose-tolerance tests and an increase in lipoproteins (Briggs, 1976; Briggs and Briggs, 1981). The authors further note alterations in plasma proteins and a certain action on the pituitary: basal prolactin and plasma growth hormone are enhanced, and the concentration of thyrotrophin remains unchanged but adrenocorticotrophin is suppressed. Also, the pattern of plasma androgen is altered. The levels of plasma Cortisol and to a lesser extent of plasma aldosterone are increased.

Plants having antifertility effects in females

Most of these plants have either anti-implantation, uterine stimulant or abortifacient action. Bioassays which can be used to evaluate the alleged fertility regulating effects of the plants include in vitro evaluation using the rat uterus and confirmation in the 29-day pregnant rabbit for utero-evacuant activity. A third bioassay involves testing for anti-implantation effects, initially in rats, with confirmation in hamsters.

The active principles of some Fabaceae, such as Sophora occidentalis L., Sesbania bispinosa (Jacq.) Wight and Cajanus cajan (L.) Mill., were found to be isomeric quinolizidine alkaloids; they had some value as ecbolics but were ineffective for inducing abortion during the early stages of pregnancy (Farnsworth et al., 1975b). The activity of a principle of another Fabaceae, Pisum sativum L. (the common garden pea), m-xylohydroquinone (2,6-dimethylhydroquinone) has been studied extensively in women in India. However it proved to be only about 60% effective in preventing conception in the groups studied and was abandoned as a potentially useful fertility regulator (Sanyal, 1956, 1958; Sanyal and Rana, 1959; Furuya and Galston, 1965).

From numerous reviews on plants as sources of antifertility agents (Casey, 1960; Chaudhury, 1966; Vohora et al., 1969; Brondegaard, 1973; Barnes et al., 1975; Prakash and Mathur, 1979 and many others), Farnsworth et cl. (1975a, b) concluded that for the estimation of the potential value of new antifertility agents results from animal experiments were difficult to interpret, and a WHO meeting was convened in Mexico City in 1976 in order to develop a programme for a more systematic evaluation of antifertility plants. Priorities were set on the study of male contraceptives and 'morning after' and anti-implantation agents for use in the female.

In January 1978, six collaborating centres in different parts of the world were selected to contribute to the collection, testing and subsequent identification of antifertility agents from plants identified by an extensive computer analysis of published information (Soejarto et al., 1978). In further research in the course of the fulfilment of this worldwide programme, Bingel and Farnsworth (1980) pointed out that plants tending to interfere with implantation in the female (Naqvi and Warren, 1971; Morris and van Wagenen, 1973; Mishra et al., 1979) and those which may interfere with sperm formation and/or maturation in the male (Setty et al., 1976; Banerji et al., 1979) were those of particular interest to the antifertility programme. They found, however, that there are other factors to be considered.

Abortion or interception has frequently been found to be caused by cytotoxic plant constituents (Hartwell, 1976; Pakrashi et al., 1977). Many cytotoxic agents have been found to be anti-spermatogenic, for example, vinblastine and vincristine from Catharanthus roseus (Fern, 1963) and cardenolides from Calotropis procera, (Atal and Sethi, 1962; Vilar, 1974; Atal, 1980). The use of such drugs entails the danger that neoplastic agents may induce chromosomal aberrations and thus not only affect the sperm number but also cause other adverse reactions. Therefore the usefulness of cytotoxic agents for interrupting pregnancy is limited by their potential toxicity to the maternal organism and by the possibility of their producing teratogenic effects in the surviving fetuses, when given in marginal doses or at marginal times (Morris, 1970, in Bingel and Farnsworth, 1980). In the case of Abrus precatorius, abortive action seems to be limited to a steroidal oil and the teratogenic action to an aqueous extract of the protein fractions. Separation of these two effects may be possible by extraction.

Cyanogenic agents have also been noted to influence reproduction and neonatal development in rats (Dlusi et al., 1979) and rabbits (Eshiett et al., 1980). Also, a correlation between the spermicidal activity and the haemolytic index of certain plant saponins has been reported (Ad Elbary and Nour, 1979).

Kamboj and Dhawan (1982) endeavoured to reduce the list of Indian plants used for contraceptive purposes in females. They reviewed the literature on these plants published in India together with the unpublished data of the Central Drug Research Institute and gave most attention to the identification of plants with interceptive properties. They concluded that in many cases the evaluation showed results which varied from no activity to 100% activity for the same plant. Lack of proper botanical authentication and inconsistent results in repeat tests or lack of facilities were indicated as possible reasons. (They also suggested modification to the feeding schedule of the plants to be screened.)

Of the plants examined, Kamboj and Dhawan (1982) excluded follow-up of Hibiscus rosa-sinensis and Plumbago zeylanica on the basis of preliminary toxicity studies. They recommended, in order of priority, follow-up of Achyranthes aspera (stembark), Sapindus trifoliatus (seed) and Abrus precatorius (seed). Because of similarities in the climates of parts of India and tropical West Africa, a certain number of these plants also occur in the area discussed in this book, and a selection of them (and of those indicated by Farnsworth et al. (1983)) is listed in Table 6.1. It should be noted that the African plants will have to be examined for analogy in chemistry and action with the Indian varieties.

Plants having antifertility effects in males

Plants used for regulating male fertility have to interfere either with sperm production and maturation (Parkhurst and Stolzenberg, 1975) or with sperm storage or with their transport in the female genital tract. Ideally, these plants should not exert any effects on non-reproductive systems and enzymes. With these objectives in mind, Bingel and Farnsworth (1980) selected from plants found worldwide a number of promising and interesting species (see also Farnsworth and Waller, 1982). Of these, those species which are found in tropical West Africa are listed in Table 6.2. Of course it will have to be checked whether the plants growing in West Africa have the same constituents and properties as the same species grown elsewhere.

As well as being included in the tables, a few antifertility plants which are of particular interest to West Africa have been described in more detail.

Fig. 6.1. Albizia lebbeck Benth.

Fig. 6.1. Albizia lebbeck Benth.

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