Hormones in endocrine and metabolic disorders

Hormones are chemical messengers that transmit information from one cell to another to coordinate growth, development, and reproduction in the body. They are synthesized in a limited number of tissues and secreted into the circulation, where they are transferred to a targeted tissue. Here they bind with receptor proteins that possess a recognition site, which binds hormones with high specificity, and an activity site, which trans- lates the information received into a biochemical message.

Two classes of hormones operate via two types of receptors. Peptide hormones and amino acid–derived hormones act via receptors located in the cell membrane and often activate second messengers that amplify and distribute the molecular information. Steroid hormones and thyroid hormones interact with intracellular receptors that bind to DNA recognition sites to regulate transcription of target genes. They change the concentra- tion of cell proteins, primarily enzymes, which results in a change in the metabolic activity of the cell.

The secretion and production of hormones in the body are generally under close regulatory control. As illustrated in Figure 8.1 , they involve a feedback control of production and a hormonal cascade that begins with signals in the central nervous system followed by hormone secretion by the hypothalamus, pituitary, and end target gland. Hormones produced by the end target gland (e.g., sex hormones and corticosteroids) feed back on the hypothalamic–pituitary system to regulate their own rates of synthesis. When the endogenous pool of a particular hormone increases to a certain level in the plasma, the hypothalamus or the pituitary gland stops production of the specific releasing factor or tropic hormone, which in turn stops production of the particular hormone by the target gland.

The endogenous pool of hormone is also dependent on the rates of metabolism and excretion of the hormone. Because of feedback control of hormone secretion, changes in rates of hormone degradation generally do not cause endocrine pathology, provided the feedback control mechanisms that regulate synthesis are intact. For example, in severe liver disease, the degradation of corticosteroids by the liver is impaired; however, the endogenous pool level of corticosteroids does not increase above the

152 Tyler's herbs of choice: The therapeutic use of phytomedicinals

Hypothalamus CNS

(limbic system) Corticotropin

Gonadotropin releasing

Thyrotropin Prolactin

releasing releasing

Feedback regulation

Pituitary Gland

Adrenocorticotropic Thyroid-Stimulating

Folicle-Stimulating Hormone (TSH)

Tropic

Hormone (ACTH)

Hormones Adrenal

Prolactin

Luteinizing

Hormone (LH) Hormone (FSH)

Ovary cortex

(Corpus Ovary Target luteum)

(Follicle) Glands Endogenous

Corticosteroids Thyroid hormones

Testosterone Progesterone Estradiol Hormone Pool

Metabolic Metabolic eﬀects

Reproduction eﬀects

Lactation

metabolic eﬀects

Figure 8.1 Hormonal cascade and feedback regulation in the production of hormones.

normal range because secretion of ACTH by the pituitary is inhibited (Figure 8.1). 1

The most prevalent endocrine disorders result from hormone deficien- cies. In addition to the involutional changes of the gonads associated with the aging process, a variety of disease states impairs or destroys the ability of endocrine glands to synthesize and secrete hormones. These include defects in gland development, genetic defects in biosynthetic enzymes, immune mediated destruction, neoplasia, infections, nutritional deficits, and vascular insufficiency. As a consequence, endocrine therapy often involves hormone replacement such as the use of insulin to treat diabetes or estrogen to alleviate the symptoms of menopause. 1

In general, the ability of a hormone to react with its particular receptor is very specific and is associated with rigid chemical structure require- ments for the hormone molecule in order for it to fit the receptor and produce a biological effect. An analogy often used to describe this phe- nomenon is the precise configuration required for a key to fit and open a lock. For this reason, hormone replacement therapy usually involves natural hormones or chemicals very closely related in structure.

Unfortunately, many people are under the misconception that plants produce steroid hormones. This erroneous idea probably stems from the fact that plants such as the wild yam (Dioscorea) and soya bean produce steroid compounds that have no hormonal activity but, rather, serve as

Chapter eight: Endocrine and metabolic problems 153 starting materials in the chemical synthesis of steroid hormones. The case

of progesterone and wild yam is illustrative of the extreme foolishness that can result from an incomplete understanding of the biology, chemis- try, and production of steroid hormones. Diosgenin, a steroidal sapogenin produced in wild yam, is a starting material for the chemical synthesis of progesterone. 2,3 Diosgenin and wild yam are not known to exert estro-

genic activity in humans, yet wild yam herbal products are falsely adver- tised and sold to treat conditions requiring progesterone replacement. 4

Estrogenic activity, on the other hand, is unique in that it does not require a strict structural configuration as do the other sex hormones and the corticosteroids. The estrogen receptor has been found to accommo- date a diverse array of aromatic structural types that do not contain the steroid nucleus. Medicinal chemists have made available a large number of therapeutically useful nonsteroidal estrogen agonists such as diethyl- stilbesterol (DES), which is used as a postcoital contraceptive agent, and antagonists such as tamoxifen, used in the treatment of breast cancer. In addition, the constituents of many plants have weak estrogenic activity and are called phytoestrogens. Phytoestrogens are found in more than twenty different classes of phytochemicals, including cooumestans, isoflavones, lignans, resorcyclic acid lactones, including the fungal mycotox- ins (zearalenones and their derivatives) produced by molds of Fusarium species that commonly infect corn, wheat, barley, sorghum, hay, and even

ginseng. 5 Prominent examples of these are the isoflavonoid genistein, found in soy beans and other legumes, and the coumarin derivative coumesterol, found in a number of different legumes.

Considered the most potent of phytoestrogens, coumestrol is actually the collective name for the twenty or so coumestans thus far identified. It is considered to be thirty to one hundred times more active as an estrogen than the isoflavones, about two hundred times less potent

than estrone, and almost three thousand times less potent than DES. 6 In vitro studies with these compounds have shown a weak binding to the estrogen receptor—roughly 0.4 and 13 percent, respectively—relative to

100 percent binding affinity for the natural ligand estradiol. 7 Assays with hepatocytes demonstrate that phytoestrogens have potencies ranging between one thousand and two thousand times less than estradiol; however, this low potency does not mean phytoestrogens will be inactive in therapy. Because of their high therapeutic index, much larger doses can

be administered. 8 The revelation by the Women’s Health Initiative that hormone replacement therapy (HRT) with equine estrogen, combined with progestin, was associated with a significantly increased risk of developing breast cancer 9 led to 56 percent of women discontinuing use of HRT. That event gen- erated much increased interest in alternative treatments for menopausal symptoms such as hot flashes, anxiety, insomnia, and osteoporosis.

154 Tyler's herbs of choice: The therapeutic use of phytomedicinals Phytoestrogens appeared a promising alternative to HRT and research

into their activity consequently increased. More than twenty classes of phytochemicals are natural human estrogen receptor (ER) ligands; the five most potent are steroids, polyketides (zearalenones), alkylated flavanones, isoflavones, and phenylbenzofurans. The most researched of these compounds have been the isoflavones, identified as the phytoestrogenic principles of soy and red clover (Trifolium pretense L.) and responsible for observed in vitro and in vivo activity sug- gestive of clinical potential. However, clinical data on phytoestrogens are sparse. In an exhaustive review of the literature through 2003, only two clinical trials were identified concerning evaluation of another promising phytoestrogenic plant, Humulus lupulus L. (hops; see discussion in Chapter 7 ). A recent review of the pharmacognosy of hops emphasizing

its estrogenic properties concluded that “hops preparations which contain 8-prenylnaringenin (8-isopentenylnaningenin) or hopein must be considered estrogenic.” 10

It has yet to be determined, however, whether such preparations can have beneficial hormonal activity when consumed orally by humans. No officially recognized standards exist for estrogenic formulations of hops.

An interesting phytoestrogenic controversy regarding conflict- ing reports of ginseng’s estrogenic activity has been explained on the basis of fungal contamination: Root extracts of Asian (Panax ginseng) and

American (P. quinquefolius) ginseng were found to bind to both ER α and ER β, with two to three times greater affinity for the latter. Subsequent analysis of the extracts revealed significant ER binding attributable to zearalenone, the estrogenic mycotoxin produced by several Fuarium fungal species. The ERs showed no binding affinity for ginsenoside Rb1, the major ginsenoside of both ginseng species, or for Rg1, a prominent ginsenoside in Asian ginseng. 5

Plant constituents may have hormonal activity through mechanisms different from replacement therapy. As can be noted in Figure 8.1 , many places in the hormonal cascade can be influenced by the inhibitory activity of a plant constituent. One of these is the endogenous hormone pool. The level of particular hormones in the pool is governed by enzymes that promote either the synthesis or degradation of hormones. Compounds that inhibit these enzymes, thus increasing or decreasing the amount of hormone, would appear to be acting as a hormone or an antihormone. 11

For example, in the case of the undesirable mineralocorticoid activity of licorice ( Chapter 3 ), the active constituent glycyrrhetinic acid inhibits 11 β-hydroxysteroid dehydrogenase, an enzyme that degrades hydrocortisone (a compound with mineralocorticoid activity) to cortisone, which has very little mineralocorticoid activity. Inhibition of this conversion increases the level of hydrocortisone in the endogenous corticosteroid pool, with a subsequent increase in undesirable

Chapter eight: Endocrine and metabolic problems 155 mineralocorticoid activity. The net level of corticosteroids in the endog-

enous pool is not increased, so there is no influence on the feedback regulation loop of the hormonal cascade. The general outcome of the use of licorice would lead one to conclude that it contains an active constituent that has intrinsic mineralocorticoid activity, but it actually inhibits a degradative enzyme and indirectly produces a mineralocorticoid effect by upsetting the balance of hydrocortisone to cortisone found in the endogenous hormone pool.

Hormones in endocrine and metabolic disorders