Estrogens, Progestins, & Hormone Therapy Lorelei Vandiver Chem 5398 March 25, 2008
Outline • Estrogens • History • Synthesis • Receptors • Medical Uses • Progestins • History • Synthesis • Receptors • Medical Uses • Hormone Therapy • Menopause • Types of HT
Steroid Synthesis Picture taken from wikipedia.com
Roles in both males and females Males: growth spurt, skeletal maturation, epiphyseal closure, maturation of sperm. Females: development of female sex organs and secondary sex characteristics, regulate menstrual cycle, skeletal maturation The most prevalent forms of human estrogen are estradiol and estrone. Both are produced and secreted by the ovaries, although estrone is also made in the adrenal glands and other organs. Estrogens
Estrogen History • 1900: Knauer found that ovarian transplants prevent symptoms of gonadectomy. • 1923: Allen and Doisy devised a bioassay for ovarian extracts. • 1925: Frank and associates detected an active sex principle in the blood of sows. • 1926: Loewe and Lange discovered that a female sex homone varied throughout menstrual cycle. • 1928: Zondek reported excretion of estrogen during pregnancy. • 1929: Estrogen crystallize by Butenandt and Doisy • 1941: FDA approval of estrogen therapy for menopausal symptoms.
Aromatase Estradiol Estriol Androstenedione Aromatase Estrone Testosterone Estrogen Synthesis - in the body • Synthesis of estrogens mainly in the ovary, by the synthesis of androstenedione from cholesterol. Androstenedione is then converted to estrone or estradiol, either immediately or through testosterone. This process is catalyzed by the enzyme aromatase.
Estrogen Receptors • Estrogens act as signaling molecules by interacting with specific target cells. • Include tissues of the breast, uterus, brain, heart, liver, and bone. • These target cells have binding sites called estrogen receptors. • There are two estrogen receptors that are normally found in the cell’s nucleus: ER α and ER β.
Estrogen Receptors cont. • The receptor changes conformation due to the dissociation of heat shock proteins after estrogen binds to it. • The receptor undergoes dimerization in order for increased affinity to DNA. • This estrogen-receptor complex can now bind to specific DNA sites, called estrogen response elements (EREs). • Genes are activated to produce messenger RNA, which guide the synthesis of new proteins, determined by the cell type.
Antiestrogens & SERMs • Antiestrogens are substances that block the action of estrogen (antagonists). • Bind to estrogen receptors so that estrogen cannot react with its receptor, and genes cannot be activated.
Antiestrogens & SERMs • SERMs (selective estrogen receptor modulators) selectively stimulate or inhibit specific ERs in target tissues. • This is possible because each ER in different tissues differ slightly in their chemical structure.
Medical Uses of Estrogen • Oral contraceptives • Menopausal hormone therapy • Vaginal atrophy • Hypoestrogenism • Wound healing • Experimental treatment of bulimia nervosa
Negative Implications - Estrogen • Estrogen has been shown to place a role in the development of uterine and breast cancer. • When estrogen binds to its receptor in breast and uterine tissues, its main role is in cell proliferation (lactation and pregnancy). This cell proliferation can lead to cancer. • Treatment of breast cancer patients with an antiestrogen resulted in a 25% decrease in mortality and a 45% decrease in incidence.
Progestin History • 1933: Corner and Allen isolated “progestin” from corpora lutea of sows • 1934: Same hormone found independently by European scientists, called it “luteo-sterone” • 1935: The groups compromised by naming the hormone “progesterone” • Sometimes progestin is used to refer to synthetic progesterone, and progesterone refers only to what is naturally made in the body.
Progestin History cont. • 1940s: Russel Marker synthesized progestin from plant product (diosgenin) • 1950s: Carl Djerassi and Frank Colton synthesized first orally active progestins
Progesterone Cholesterol Pregnenolone Progestin Synthesis
Progesterone Receptors • There are two Progesterone Receptors (PR): PR-A and PR-B. • Progesterone (or an antiprogestin) bind to the PR, producing a conformational change that increases DNA affinity. • The receptor changes conformation due to the dissociation of heat shock proteins after estrogen binds to it. • The receptor undergoes dimerization in order for increased affinity to DNA. • This complex can now bind to specific DNA sites, called progesterone response elements (PREs).
Inhibitors of Progestins • Binding anti-progestins to the PRs produces a delay in endometrial maturation and postpones the appearance of the implantation window. • Anti-Progestins • Mifepristone, used in termination of pregnancy. • PRMs – Progesterone receptor modulators
Medical Uses for Progesterone • Oral Contraceptives – with estrogen • Facilitate pregnancy: In-Vitro Fertilization • May lower risk of preterm birth • Investigated as treatment of multiple sclerosis • Prevention of long-term brain damage • Hormone Therapy
Menopause • Estrogen and progesterone levels decline to a point where pregnancy is no longer possible. • Usually occurs in late 40s, early 50s. • Since estrogen plays other roles within the body, other systems are affected.
Symptoms • Hot flashes • Changing sleep patterns • Emotional changes (mood swings) • Headaches • Heart Palpitations • Generalized Itching
Phases of Menopause • Perimenopause • Fluctuation in hormone levels • Can last 2-8 years • Menopause • Estrogen levels drop • 1 year after cessation of menstrual cycle • Postmenopause • Estrogen levels continue to drop • Miscellaneous health concerns begin
Hormonal Therapy • Use of estrogen has shown significant benefits • Reduction in loss of bone mass (osteoporosis) • Decreased risk of cardiovascular disease • Positive effect on cognitive function • Alleviates vasomotor symptoms of menopause • Progestins used to counteract negative implications of cell proliferation and weight gain
Types of HRT • Estrogen-Progestin combination pills • Transdermal Patches • Oral Progestin • Progestin IUDs
Combination Pills • Activella (estradiol / norethindrone acetate) • 28 day pack • 2:1 estradiol to norethindrone acetate
Transdermal Patches • CombiPatch (estradiol / norethindrone acetate) • Alcohol free, 3 layers • Lasts 3.5 days
Oral Progestin • Used with an estrogen-only preparation • Provera (medroxyprogesterone) • Prevents unchecked growth of endometrium due to estrogen
Progestin IUDs • Used with an estrogen-only preparation • Mirena (levonorgestrel) • Lasts up to 5 years
Osteoporosis & Menopause • Estrogen aids to maintain bone mineral density (BMD). • There is a positive relation between maintenance of bone mass and HT with estrogen. • Decrease rates of wrist, non-vertebral, vertebral, and hip fractures. • Raloxifene – SERM that functions like estrogen within bone.
Cardiovascular impact • When estrogen binds to its receptors within the liver, it causes cholesterol in the form of lipoproteins to be synthesized. • Cholesterol is in the form of LDL or HDL. Estrogen encourages HDL (good cholesterol) to be made and inhibits the formation of LDL (bad cholesterol), and thereby lowers the risk of cardiovascular disease.
Cognitive function • Both ER α and ER β are found throughout the brain. • The expression and the activity of these receptors indicate improvement in cognitive function. • Data has demonstrated that estrogen users had a 30% decrease risk of developing Alzheimer’s disease.
Conclusion • Estrogen and Progestin should be used in conjunction with each other for maximum benefits and minimum risks. • As technology improves, there will come a time when a harm-benefit analysis of estrogen use may be performed to tailor a treatment plan to individual patients, especially in Hormone Therapy. • Further research is needed to develop better SERMs in order to selectively target specific tissue types in cancer treatment and Hormone Therapy to minimize risks.
References • The Pharmacological Basis of Therapeutics by Goodman and Gilman • “Menopause: Developing a rational treatment plan” by Vitiello, et al. • “Perspective: Female Steroid Hormone Action” by Dr. Orla Conneely • “History of Contraception” by Potts and Campbell • <http://wikipedia.com> • “Progesterone vs Progestin” by Dr. Steven Hotze • <http://www.cancer.gov> • “Advances in HRT: Weight benefits of drospirenone, a 17α –spirolactone-derived progestogen” by Foidart, et al. • “Estrogens and the skin” by Brincat, et al. • “The effect of estrogen on appetite” by Geary. • “Mechanism of action and clinical effects of antiprogestins on the non-pregnant uterus” by Spitz, et al. • <http://www.providence.org>