Hormone Therapy. Menopause. Transgender Surgery. Adrenal Hormones

Hormones are substances formed in one organ of the body and transported in the blood to another where they regulate and control physiological activity. The term hormone was coined in 1905 by William B. Hardy from the Greek meaning ‘‘arouse to activity.’’ English physiologist Ernest H. Starling and Sir William Bayliss discovered the first hormone in 1902 and named it secretin. Chemically, hormones are divided into three classes: amino acid derivatives, peptides, and steroids. The purpose of hormone therapy is to provide or maintain physiological homeostasis with natural or synthetic hormone replacement.

Menopause. Perhaps the most familiar type of steroid hormone therapy is estrogen replacement therapy (ERT) for women whose ovaries have been removed surgically or women who have symptoms related to menopause. The first estrogen drug, under the trade name Premarin, was available in injectable form in 1942. The pill form gained popularity as the ‘‘medicalization’’ of menopause increased.

The hormone was derived from the urine of pregnant mares. When the relationship between osteoporosis, hip fracture, and low estrogen levels was recognized, ERT was recommended for all women. The ‘‘baby-boomer’’ generation (those born between 1946 and 1964) was particularly receptive to ERT promotion, and by the end of the century one third of postmenopausal women in the U.S. were taking some kind of hormone replacement therapy.

In 1975, research indicated that unopposed estrogen raised the rate of endometrial cancers. Progesterone was added to estrogen, and the treatment became known as HRT (hormone replacement therapy). By the year 2000, esterified estrogens, synthetic estrogen from plant sources, and combinations with testosterone and progestins were prescribed as pills, transdermal skin patches, or intravaginal applicators. Studies early in the twenty-first century, however, determined that although these drugs were safer, they did not provide sufficient protection against osteoporosis or cardiovascular disease in women to warrant the risks of therapy.

Transgender Surgery. In 1930, Danish artist Einer Wegener underwent the first documented gender reassignment surgery and became Lily Elbe. Gender and sex, taboo topics for much of the century, became important research concerns in the 1960s. John Money began his longitudinal studies on children born with ambiguous genitalia (intersex individuals).

Understanding how male and female sex hormones worked on the brain paved the way for more sophisticated hormone therapies before and after gender reassignment surgery.

Androgens are administered to biological females, and estrogens, progesterone, and testosterone-blocking agents (anti-androgens) are given to biological males, either orally, transdermally, or by injection, to stimulate anatomical changes. Orchiectomy (removal of the testicles) may mean that feminizing hormone dosages can be reduced. Unfortunately, follow-up studies revealed high morbidity and mortality rates, and the reasons for this are unknown. Although one can correlate hormone therapy with these rates, it is difficult to isolate causal factors because of the complex relationship between physiological and psychological processes.

Prostate Cancer. Hormone therapy may be initiated to treat prostate cancer following, or in addition to, surgery or radiation therapy. The hormones used to treat prostate cancers are also anti-androgens, substances antagonistic to the male hormones. Estrogen and diethylstilbestrol (DES) were used until the late 1970s when some synthetic compounds were introduced. In 1987 Zoladex, a drug that interferes with the production of testosterone, was tested to replace DES.

Cyproterone acetate (a type of anti-androgen) and Estracyt or Emcyt (a combination of estradiol and nitrogen mustard) were found to be effective when estrogen therapy failed. A synthetic hormone to treat prostate cancer, Lupron, suppresses the formation of steroids in the body. Paradoxically, it has also been prescribed for the treatment of endometriosis in women.

Human Growth Disorder. Human growth hormone (HGH, somatotropin) was discovered by Herbert Evans in 1921, but it was not used in the U.S. until 1958 to treat certain kinds of dwarfism in children related to hormone deficiency. Stature deficits were virtually eliminated with this hormone, produced from human pituitary glands from cadavers. Unfortunately, the deaths of four children were traced to cadavers in which Creutzfeldt-Jacob disease infectious tissue was present (a new variant of Creutzfeldt-Jacob disease became known in the 1990s as the human form of mad cow disease), and in April 1985 all hormone production using cadavers ceased.

In October of that year, a biosynthetic hormone, somatrem, was produced using recombinant DNA technology. For thousands of children dependent on continued therapy for optimum growth, an unlimited supply of HGH could be produced. As with HRT for women, questions have been raised about the use and potential misuse of this hormone for human engineering.

Thyroid Deficiency. At the turn of the century, George Murray prepared an extract of thyroid from a sheep and injected it into a woman with myxedema, a severe form of thyroid deficiency, and the patient improved. Twenty-eight years later, he succeeded in making an oral preparation. Two hormones, thyroxine (T4), isolated in 1914, and triiodothyronine (T3), affect growth and metabolism, and both are controlled by thyrotropin, or thyroid stimulating hormone (TSH), produced by the pituitary gland. In 1910 the relationship between the thyroid gland and endemic goiter and iodine was discovered.

When there is insufficient thyroid hormone, one cause of which is insufficient iodine in the diet, the body overproduces thyrotropin, causing enlargement of the thyroid gland; the condition is known as goiter. Replacement therapy suppresses thyrotropin, and the goiter shrinks. Despite the fact that thyroid and iodine supplements have been available for 50 years, endemic goiter and cretinism still occur worldwide.

Adrenal Hormones. Prior to the twentieth century, Addison’s disease and its relationship with the adrenal glands were well known. But it was not until the 1930s that a great deal of interest was generated with regard to adrenocorticotropic hormone (ACTH). Deficiencies affected electrolyte balance, carbohydrate metabolism, hypoglycaemia, and sodium loss. It was postulated that two hormones were secreted by the adrenals: mineralocorticoids and glucocorticoids (salt and sugar hormones).

Harvey Cushing described a syndrome in which too much ACTH was secreted. When the first extract of the adrenal gland was prepared in 1930, it was found to contain 28 different steroids, and five were biologically active. Adrenal cortex substance was of interest during World War II because of its effect in reducing the stress of oxygen deprivation. However, cortisone, the ‘‘anti-stress hormone,’’ soon became the miracle drug of the twentieth century for treatment of arthritis and skin inflammations.

In 1952, hydrocortisone, with fewer side effects, was developed using biosynthesis. By the 1960s, cortical steroids were being used for over 150 medical applications. Since the 1960s, technology has been directed at developing non-steroidal anti-inflammatory therapies.

Prostaglandins. In the mid-1930s, von Euler found that when the active substance of seminal fluid was injected into laboratory animals, it lowered their blood pressure. He named it prostaglandin. For the next thirty years his Swedish colleagues continued this work and discovered that prostaglandin was really four substances composed of fatty acids.

This research led to the discovery of prostacyclin and thromboxane, hormones that have reciprocal actions on platelets. Prostacyclin has been used to treat circulatory problems. Flolan, a British product, is used to prevent blood from clotting in bypass machines.

Insulin. In 1921, Frederick Banting and Charles Best, two Canadian physiologists, were attempting to find a cure for diabetes mellitus. Their research on dogs involved removing the pancreas, waiting for symptoms of diabetes to develop, then injecting the animals with insulin. Previous experiments by others failed because the hormone degraded when taken orally. From the 1920s until the early 1980s, insulin was produced from the pancreases of pigs.

In 1973, scientists at the Massachusetts Institute of Technology paved the way for synthetic insulin when they invented a technique for cloning DNA. In 1978 Genentech cloned the gene for synthetic insulin, and in 1982 the USDA approved an insulin derived from recombinant DNA called Humulin. Since that time, a disposable insulin pen has been developed to take the place of a syringe and vial. Other technologies include jet injectors, an external insulin pump, implantable insulin pumps, and insulin inhalers. Oral antidiabetic agents called sulfonylureas were developed in 1994.

Another oral product, troglitazone, used concomitantly, was removed from the market in 1997 because of liver toxicity. In 2000, Eli Lilly, the original pharmaceutical company for the manufacture of insulin, announced a research partnership with Generex Biotechnology to develop another oral (buccal) form of insulin.

Negative Consequences. As previously noted, some of the technologies that have allayed suffering and prolonged life in the twentieth century have also been misused. In the 1990s, synthetic HGH was marketed to athletes to increase body strength and to adults as the ‘‘anti-aging hormone.’’

Many of these nonmedical applications had disastrous consequences. Controversies with HRT continued as some women believed the ‘‘hot flashes’’ and sleep disorders they experienced beginning in perimenopause could only be relieved with hormone therapy, while others simply considered estrogen useful to maintain a youthful appearance. On the other hand, for the millions of children and adults who have benefited from insulin, there is no controversy about hormone therapy.