Estrogens, Progestins, & Hormone Therapy Lorelei Vandiver Chem 5398 March 25, 2008

Outline Estrogens Estrogens –History –Synthesis –Receptors –Medical Uses Progestins Progestins –History –Synthesis –Receptors –Medical Uses Hormone Therapy Hormone Therapy –Menopause –Types of HT

Steroid Synthesis Picture taken from wikipedia.com

Estrogens Roles in both males and females 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. 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.

Estrogen History 1900: Knauer found that ovarian transplants prevent symptoms of gonadectomy. 1900: Knauer found that ovarian transplants prevent symptoms of gonadectomy. 1923: Allen and Doisy devised a bioassay for ovarian extracts. 1923: Allen and Doisy devised a bioassay for ovarian extracts. 1925: Frank and associates detected an active sex principle in the blood of sows. 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. 1926: Loewe and Lange discovered that a female sex homone varied throughout menstrual cycle. 1928: Zondek reported excretion of estrogen during pregnancy. 1928: Zondek reported excretion of estrogen during pregnancy. 1929: Estrogen crystallize by Butenandt and Doisy 1929: Estrogen crystallize by Butenandt and Doisy 1941: FDA approval of estrogen therapy for menopausal symptoms. 1941: FDA approval of estrogen therapy for menopausal symptoms.

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. Estradiol Estriol Estrone Testosterone Androstenedione Aromatase

Estrogen Receptors Estrogens act as signaling molecules by interacting with specific target cells. 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. 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 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. 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). 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. Genes are activated to produce messenger RNA, which guide the synthesis of new proteins, determined by the cell type.

Estrogen Receptors

Antiestrogens & SERMs Antiestrogens are substances that block the action of estrogen (antagonists). 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. 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 Oral contraceptives Menopausal hormone therapy Menopausal hormone therapy Vaginal atrophy Vaginal atrophy Hypoestrogenism Hypoestrogenism Wound healing Wound healing Experimental treatment of bulimia nervosa Experimental treatment of bulimia nervosa

Negative Implications - Estrogen Estrogen has been shown to place a role in the development of uterine and breast cancer. 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.

Progestins

Progestin History 1933: Corner and Allen isolated “progestin” from corpora lutea of sows 1933: Corner and Allen isolated “progestin” from corpora lutea of sows 1934: Same hormone found independently by European scientists, called it “luteo- sterone” 1934: Same hormone found independently by European scientists, called it “luteo- sterone” 1935: The groups compromised by naming the hormone “progesterone” 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. 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) 1940s: Russel Marker synthesized progestin from plant product (diosgenin) 1950s: Carl Djerassi and Frank Colton synthesized first orally active progestins 1950s: Carl Djerassi and Frank Colton synthesized first orally active progestins

Progestin Synthesis CholesterolPregnenolone Progesterone

Progesterone Receptors There are two Progesterone Receptors (PR): PR-A and PR-B. 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. 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 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. 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). 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. Binding anti-progestins to the PRs produces a delay in endometrial maturation and postpones the appearance of the implantation window. Anti-Progestins Anti-Progestins –Mifepristone, used in termination of pregnancy. PRMs – Progesterone receptor modulators PRMs – Progesterone receptor modulators

Medical Uses for Progesterone Oral Contraceptives – with estrogen Oral Contraceptives – with estrogen Facilitate pregnancy: In-Vitro Fertilization Facilitate pregnancy: In-Vitro Fertilization May lower risk of preterm birth May lower risk of preterm birth Investigated as treatment of multiple sclerosis Investigated as treatment of multiple sclerosis Prevention of long-term brain damage Prevention of long-term brain damage Hormone Therapy Hormone Therapy

Menopausal Hormone Replacement Therapy

Menopause Estrogen and progesterone levels decline to a point where pregnancy is no longer possible. Estrogen and progesterone levels decline to a point where pregnancy is no longer possible. Usually occurs in late 40s, early 50s. Usually occurs in late 40s, early 50s. Since estrogen plays other roles within the body, other systems are affected. Since estrogen plays other roles within the body, other systems are affected.

Symptoms Hot flashes Hot flashes Changing sleep patterns Changing sleep patterns Emotional changes (mood swings) Emotional changes (mood swings) Headaches Headaches Heart Palpitations Heart Palpitations Generalized Itching Generalized Itching

Phases of Menopause Perimenopause Perimenopause –Fluctuation in hormone levels –Can last 2-8 years Menopause Menopause –Estrogen levels drop –1 year after cessation of menstrual cycle Postmenopause Postmenopause –Estrogen levels continue to drop –Miscellaneous health concerns begin

Hormonal Therapy Use of estrogen has shown significant benefits 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 Progestins used to counteract negative implications of cell proliferation and weight gain

Types of HRT Estrogen-Progestin combination pills Estrogen-Progestin combination pills Transdermal Patches Transdermal Patches Oral Progestin Oral Progestin Progestin IUDs Progestin IUDs

Combination Pills Activella (estradiol / norethindrone acetate) Activella (estradiol / norethindrone acetate) –28 day pack –2:1 estradiol to norethindrone acetate

Transdermal Patches CombiPatch (estradiol / norethindrone acetate) CombiPatch (estradiol / norethindrone acetate) –Alcohol free, 3 layers –Lasts 3.5 days

Oral Progestin Used with an estrogen- only preparation Used with an estrogen- only preparation Provera (medroxyprogesterone) Provera (medroxyprogesterone) –Prevents unchecked growth of endometrium due to estrogen

Progestin IUDs Used with an estrogen-only preparation Used with an estrogen-only preparation Mirena (levonorgestrel) Mirena (levonorgestrel) Lasts up to 5 years Lasts up to 5 years

Osteoporosis & Menopause Estrogen aids to maintain bone mineral density (BMD). Estrogen aids to maintain bone mineral density (BMD). There is a positive relation between maintenance of bone mass and HT with estrogen. 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. 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. 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. 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. Both ER α and ER β are found throughout the brain. The expression and the activity of these receptors indicate improvement in cognitive function. 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. 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. 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. 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 The Pharmacological Basis of Therapeutics by Goodman and Gilman “Menopause: Developing a rational treatment plan” by Vitiello, et al. “Menopause: Developing a rational treatment plan” by Vitiello, et al. “Perspective: Female Steroid Hormone Action” by Dr. Orla Conneely “Perspective: Female Steroid Hormone Action” by Dr. Orla Conneely “History of Contraception” by Potts and Campbell “History of Contraception” by Potts and Campbell “Progesterone vs Progestin” by Dr. Steven Hotze “Progesterone vs Progestin” by Dr. Steven Hotze “Advances in HRT: Weight benefits of drospirenone, a 17 α – spirolactone-derived progestogen” by Foidart, et al. “Advances in HRT: Weight benefits of drospirenone, a 17 α – spirolactone-derived progestogen” by Foidart, et al. “Estrogens and the skin” by Brincat, et al. “Estrogens and the skin” by Brincat, et al. “The effect of estrogen on appetite” by Geary. “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. “Mechanism of action and clinical effects of antiprogestins on the non-pregnant uterus” by Spitz, et al.