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At a glance

  • Treatment advances have increased the survival rates for children with cancer.
  • Consequences of advanced lifesaving cancer therapies may damage the endocrine system.
  • Therapeutic effects are achieved at lower peak doses of transdermal estrogen.
  • Rapid cessation of drug administration is possible with removal of the transdermal system.
Have reports about the risks associated with hormone replacement therapy influenced your prescribing habits?

Estrogen is one of the most prescribed drugs worldwide. It is used to treat menopausal symptoms and ovarian failure.1 Although estrogen replacement therapy (ERT) was approved by the FDA more than 60 years ago, the best practice in prescribing ERT remains a confusing and controversial subject.

In the fall of 2007, a 14-year-old patient with ovarian failure challenged our beliefs and our ERT prescribing practices. What we learned can be of great value to clinicians who treat both pediatric and adult patients.

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Case study

Patient history. At age 6 years, Ashley was diagnosed by pediatric oncology with acute myelocytic leukemia. She was treated with multiple rounds of chemotherapy, but these failed to cure the disease. The only intervention that could save her life was a bone marrow transplant.

In preparation for this procedure, Ashley received high-dose chemotherapy and total body irradiation. Two years after treatment, she celebrated being cancer-free, and yet the treatment that saved her life had also adversely affected her endocrine system.

Post-transplant side effects. When she was age 8 years, Ashley was referred to the pediatric endocrine service for evaluation of her short stature; her growth for age was less than the third percentile. A physical examination and laboratory results revealed growth hormone deficiency, as well as central hypothyroidism. Treatment with growth hormone and levothyroxine produced an excellent response. She remained euthyroid, and within 18 months, her growth for age was at the 25th percentile.

Ashley returned to the pediatric endocrine clinic yearly for laboratory studies and physical examinations. Although she was progressing well, she remained prepubertal. Results of her evaluation at age 13 indicated that she had made no progress. Her Tanner staging was completely prepubertal. Her luteinizing hormone (0.1 mIU/mL), follicle-stimulating hormone (2 mIU/mL) and estradiol (2.5 ng/dL) levels were low and confirmed the diagnosis of hypogonadotropic hypogonadism.

Initiating feminization in girls with this diagnosis requires the use of estrogen. Ashley and her parents were given information on ERT and encouraged to call and/or make a list of any questions they would like to have answered before beginning therapy.

Starting ERT. At age 14 years, Ashley came for her annual visit and to begin ERT. Standing beside her mother, Ashley proclaimed, “I know I need to start estrogen, and I want to go over my options. You know I am a vegetarian. I love animals, and I will not take the estrogen they get from horses. It is totally cruel. I have been on the Internet, and I want the estrogen that comes from plants.”

Over the past 10 years, there has been a rise of vegetarianism2 in the United States,3 especially among adolescent girls.4 Many patients or their parents request information on the source of their medications based on religious, moral or ethical concerns.5 Additionally, widespread use of the Internet allows providers and the lay public access to information that, in the past, was only debated in scientific communities.

Ashley was correct; the prescription awaiting her was for Premarin, a formulation of conjugated estrogens that is derived from the urine of pregnant mares. To address Ashley’s moral concerns and provide the best estrogen formulation for her required a greater understanding of this complex and evolving drug field.

Three forms of estrogen

Although estrogen sounds as if it is one hormone, it is, in fact, the name of a group of hormones. There are three basic forms of estrogen in the human female body: estrone (E1), estradiol (E2), and estriol (E3).6 Estrone is a weak form of estrogen that is most abundant in a woman’s body after menopause. Estradiol is the primary and most potent form of estrogen produced in the body before menopause. Estriol is the primary estrogen of pregnancy.

From menarche to menopause, the primary source of estrogen in normally cycling women is the ovarian follicle, which secretes estradiol daily. Estradiol induces puberty and maintains feminization.7

In most girls, puberty starts at approximately age 10 years, when the pituitary begins to secrete luteinizing hormone, which stimulates the ovaries to develop and secrete estrogen. Estrogen is responsible for enlarging the uterus and the fallopian tubes, development of the breasts, and accruing and maintaining optimal bone mineral density.

Estrogen deficiency

Estrogen deficiency can be a primary or secondary disorder. Primary estrogen deficiency results from failure of the ovary, while secondary estrogen deficiency results from failure of the pituitary to regulate the ovaries. Ovarian failure can occur in patients with genetic disorders, such as Turner syndrome; after surgical removal; or following exposure to some forms of chemotherapy or radiation to the pelvis. Pituitary failure can be caused by tumors of the central nervous system (CNS), trauma, malformations, pituitary adenomas or CNS irradiation.8

Treatment advances have increased the survival rates for children with cancer. Today, 80% are alive five years after therapy. However, significant survival benefits are also associated with short- and long-term morbidity later in life. Among the many consequences of these advanced lifesaving cancer therapies is damage to the endocrine system, resulting in short- or long-term hormone deficiencies, including ovarian failure.9

Prescribing plant-derived derivatives

Before prescribing an FDA-approved plant-derived alternative to estrogen, it is essential to review the history of estrogens, current research, the pharmacology of available ERT regimens and coverage by insurance carriers.

History of ERT. In 1942, Wyeth was the first pharmaceutical manufacturer to obtain FDA approval for ERT. Premarin, an equine-derived estrogen formulation, was marketed and approved for the treatment of menopause.10

That approval was based on clinical studies that were conducted by Wyeth and certified the safety of the product for its intended use. In 1962, Congress passed the Kefauver-Harris Amendment, also known as the “Drug Efficacy Amendment,” which required pharmaceutical manufacturers not only to prove safety but also to provide substantial evidence of effectiveness for the product’s intended use. The evidence had to consist of adequate and well-controlled studies. This was a revolutionary FDA requirement. FDA approval of estrogen provided American women with a medication that could prevent the symptoms of menopause, but few physicians were comfortable with prescribing it.

The estrogen revolution. In 1966, Robert A. Wilson, MD, published a best-selling book, Feminine Forever. Wilson, a recognized authority in the field of hormone therapy and menopause prevention, was credited with one of medicine’s most revolutionary breakthroughs — the discovery that menopause was a hormone deficiency that was curable. Estrogen replacement could restore women mentally, physically and sexually to a premenopausal state, the only difference being that they could not bear children.