Estrogens, Estrogens, Progestins, & Progestins, & Hormone TherapyHormone Therapy

Lorelei VandiverLorelei Vandiver

Chem 5398Chem 5398

March 25, 2008March 25, 2008

OutlineOutline

EstrogensEstrogens– HistoryHistory– SynthesisSynthesis– ReceptorsReceptors– Medical UsesMedical Uses

ProgestinsProgestins– HistoryHistory– SynthesisSynthesis– ReceptorsReceptors– Medical UsesMedical Uses

Hormone TherapyHormone Therapy– MenopauseMenopause– Types of HTTypes of HT

Steroid Synthesis Steroid Synthesis

Picture taken from wikipedia.com

EstrogensEstrogens

Roles in both males Roles in both males and femalesand females– Males: growth spurt, Males: growth spurt,

skeletal maturation, skeletal maturation, epiphyseal closure, epiphyseal closure, maturation of sperm.maturation of sperm.

– Females: development Females: development of female sex organs of female sex organs and secondary sex and secondary sex characteristics, characteristics, regulate menstrual regulate menstrual cycle, skeletal cycle, skeletal maturationmaturation

The most prevalent The most prevalent forms of human forms of human estrogen are estrogen are estradiol and estradiol and estrone. Both are estrone. Both are produced and produced and secreted by the secreted by the ovaries, although ovaries, although estrone is also made estrone is also made in the adrenal glands in the adrenal glands and other organs. and other organs.

Estrogen HistoryEstrogen History

1900: Knauer found that ovarian transplants 1900: Knauer found that ovarian transplants prevent symptoms of gonadectomy.prevent symptoms of gonadectomy.

1923: Allen and Doisy devised a bioassay for 1923: Allen and Doisy devised a bioassay for ovarian extracts.ovarian extracts.

1925: Frank and associates detected an active sex 1925: Frank and associates detected an active sex principle in the blood of sows.principle in the blood of sows.

1926: Loewe and Lange discovered that a female 1926: Loewe and Lange discovered that a female sex homone varied throughout menstrual cycle.sex homone varied throughout menstrual cycle.

1928: Zondek reported excretion of estrogen 1928: Zondek reported excretion of estrogen during pregnancy.during pregnancy.

1929: Estrogen crystallize by Butenandt and Doisy1929: Estrogen crystallize by Butenandt and Doisy 1941: FDA approval of estrogen therapy for 1941: FDA approval of estrogen therapy for

menopausal symptoms.menopausal symptoms.

Estrogen SynthesisEstrogen Synthesis - in - in the bodythe 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

EstriolEstrone

Testosterone

Androstenedione

Aromatase

Aromatase

Estrogen ReceptorsEstrogen Receptors

Estrogens act as signaling Estrogens act as signaling molecules by interacting molecules by interacting with specific target cells.with specific target cells.– Include tissues of the Include tissues of the

breast, uterus, brain, heart, breast, uterus, brain, heart, liver, and bone.liver, and bone.

These target cells have These target cells have binding sites called binding sites called estrogen receptors. estrogen receptors. – There are two estrogen There are two estrogen

receptors that are normally receptors that are normally found in the cell’s nucleus: found in the cell’s nucleus: ER ER αα and ER and ER ββ..

Estrogen Receptors Estrogen Receptors cont.cont. The receptor changes conformation due The receptor changes conformation due

to the dissociation of heat shock to the dissociation of heat shock proteins after estrogen binds to it. proteins after estrogen binds to it.

The receptor undergoes dimerization in The receptor undergoes dimerization in order for increased affinity to DNA.order for increased affinity to DNA.

This estrogen-receptor complex can now This estrogen-receptor complex can now bind to specific DNA sites, called bind to specific DNA sites, called estrogen response elements (EREs).estrogen response elements (EREs).

Genes are activated to produce Genes are activated to produce messenger RNA, which guide the messenger RNA, which guide the synthesis of new proteins, determined synthesis of new proteins, determined by the cell type.by the cell type.

Estrogen ReceptorsEstrogen Receptors

Antiestrogens & Antiestrogens & SERMsSERMs

Antiestrogens are Antiestrogens are substances that substances that block the action of block the action of estrogen estrogen (antagonists).(antagonists).– Bind to estrogen Bind to estrogen

receptors so that receptors so that estrogen cannot estrogen cannot react with its react with its receptor, and genes receptor, and genes cannot be activated.cannot be activated.

Antiestrogens & Antiestrogens & SERMsSERMs SERMs (selective estrogen SERMs (selective estrogen

receptor modulators) selectively receptor modulators) selectively stimulate or inhibit specific ERs in stimulate or inhibit specific ERs in target tissues.target tissues.– This is possible because each ER in This is possible because each ER in

different tissues differ slightly in different tissues differ slightly in their chemical structure.their chemical structure.

Medical Uses of Medical Uses of EstrogenEstrogen

Oral contraceptivesOral contraceptives Menopausal hormone Menopausal hormone

therapytherapy Vaginal atrophyVaginal atrophy HypoestrogenismHypoestrogenism Wound healingWound healing Experimental treatment Experimental treatment

of bulimia nervosaof bulimia nervosa

Negative Implications - Negative Implications - EstrogenEstrogen

Estrogen has been shown to Estrogen has been shown to place a role in the development place a role in the development of uterine and breast cancer.of uterine and breast cancer.– When estrogen binds to its When estrogen binds to its

receptor in breast and uterine receptor in breast and uterine tissues, its main role is in cell tissues, its main role is in cell proliferation (lactation and proliferation (lactation and pregnancy). This cell proliferation pregnancy). This cell proliferation can lead to cancer.can lead to cancer.

– Treatment of breast cancer Treatment of breast cancer patients with an antiestrogen patients with an antiestrogen resulted in a 25% decrease in resulted in a 25% decrease in mortality and a 45% decrease in mortality and a 45% decrease in incidence.incidence.

ProgestinsProgestins

Progestin HistoryProgestin History

1933: Corner and Allen isolated 1933: Corner and Allen isolated “progestin” from corpora lutea of sows“progestin” from corpora lutea of sows

1934: Same hormone found 1934: Same hormone found independently by European scientists, independently by European scientists, called it “luteo-sterone”called it “luteo-sterone”

1935: The groups compromised by 1935: The groups compromised by naming the hormone “progesterone”naming the hormone “progesterone”

Sometimes progestin is used to refer Sometimes progestin is used to refer to synthetic progesterone, and to synthetic progesterone, and progesterone refers only to what is progesterone refers only to what is naturally made in the body.naturally made in the body.

Progestin History cont.Progestin History cont.

1940s: Russel Marker synthesized 1940s: Russel Marker synthesized progestin from plant product progestin from plant product (diosgenin)(diosgenin)

1950s: Carl Djerassi and Frank 1950s: Carl Djerassi and Frank Colton synthesized first orally Colton synthesized first orally active progestinsactive progestins

Progestin SynthesisProgestin Synthesis

Cholesterol Pregnenolone Progesterone

Progesterone Progesterone ReceptorsReceptors There are two Progesterone Receptors (PR): There are two Progesterone Receptors (PR):

PR-A and PR-B.PR-A and PR-B. Progesterone (or an antiprogestin) bind to Progesterone (or an antiprogestin) bind to

the PR, producing a conformational change the PR, producing a conformational change that increases DNA affinity.that increases DNA affinity.

The receptor changes conformation due to The receptor changes conformation due to the dissociation of heat shock proteins after the dissociation of heat shock proteins after estrogen binds to it. estrogen binds to it.

The receptor undergoes dimerization in order The receptor undergoes dimerization in order for increased affinity to DNA.for increased affinity to DNA.

This complex can now bind to specific DNA This complex can now bind to specific DNA sites, called progesterone response elements sites, called progesterone response elements (PREs).(PREs).

Inhibitors of Inhibitors of ProgestinsProgestins Binding anti-progestins to the PRs Binding anti-progestins to the PRs

produces a delay in endometrial produces a delay in endometrial maturation and postpones the maturation and postpones the appearance of the implantation window.appearance of the implantation window.

Anti-ProgestinsAnti-Progestins– Mifepristone, used in termination of Mifepristone, used in termination of

pregnancy.pregnancy.

PRMs – Progesterone receptor modulatorsPRMs – Progesterone receptor modulators

Medical Uses for Medical Uses for ProgesteroneProgesterone

Oral Contraceptives – with Oral Contraceptives – with estrogenestrogen

Facilitate pregnancy: In-Vitro Facilitate pregnancy: In-Vitro FertilizationFertilization

May lower risk of preterm birth May lower risk of preterm birth Investigated as treatment of Investigated as treatment of

multiple sclerosis multiple sclerosis Prevention of long-term brain Prevention of long-term brain

damagedamage Hormone TherapyHormone Therapy

Menopausal Hormone Menopausal Hormone Replacement TherapyReplacement Therapy

MenopauseMenopause

Estrogen and Estrogen and progesterone levels progesterone levels decline to a point decline to a point where pregnancy is where pregnancy is no longer possible.no longer possible.

Usually occurs in Usually occurs in late 40s, early 50s.late 40s, early 50s.

Since estrogen Since estrogen plays other roles plays other roles within the body, within the body, other systems are other systems are affected.affected.

SymptomsSymptoms

Hot flashesHot flashes Changing sleep Changing sleep

patternspatterns Emotional changes Emotional changes

(mood swings)(mood swings) HeadachesHeadaches Heart PalpitationsHeart Palpitations Generalized ItchingGeneralized Itching

Phases of MenopausePhases of Menopause

PerimenopausePerimenopause– Fluctuation in hormone levelsFluctuation in hormone levels– Can last 2-8 yearsCan last 2-8 years

MenopauseMenopause– Estrogen levels dropEstrogen levels drop– 1 year after cessation of menstrual cycle1 year after cessation of menstrual cycle

PostmenopausePostmenopause– Estrogen levels continue to dropEstrogen levels continue to drop– Miscellaneous health concerns beginMiscellaneous health concerns begin

Hormonal TherapyHormonal Therapy

Use of estrogen has shown significant Use of estrogen has shown significant benefitsbenefits– Reduction in loss of bone mass (osteoporosis)Reduction in loss of bone mass (osteoporosis)– Decreased risk of cardiovascular diseaseDecreased risk of cardiovascular disease– Positive effect on cognitive functionPositive effect on cognitive function– Alleviates vasomotor symptoms of Alleviates vasomotor symptoms of

menopausemenopause Progestins used to counteract negative Progestins used to counteract negative

implications of cell proliferation and implications of cell proliferation and weight gainweight gain

Types of HRTTypes of HRT

Estrogen-Estrogen-Progestin Progestin combination pillscombination pills

Transdermal Transdermal PatchesPatches

Oral ProgestinOral Progestin Progestin IUDsProgestin IUDs

Combination PillsCombination Pills

Activella Activella (estradiol / (estradiol / norethindrone norethindrone acetate)acetate)– 28 day pack28 day pack– 2:1 estradiol to 2:1 estradiol to

norethindrone norethindrone acetateacetate

Transdermal PatchesTransdermal Patches

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

Oral ProgestinOral Progestin

Used with an Used with an estrogen-only estrogen-only preparationpreparation

Provera Provera (medroxyprogesteron(medroxyprogesterone)e)– Prevents unchecked Prevents unchecked

growth of growth of endometrium due to endometrium due to estrogenestrogen

Progestin IUDsProgestin IUDs

Used with an estrogen-only Used with an estrogen-only preparationpreparation

Mirena (levonorgestrel)Mirena (levonorgestrel) Lasts up to 5 yearsLasts up to 5 years

Osteoporosis & Osteoporosis & MenopauseMenopause

Estrogen aids to maintain Estrogen aids to maintain bone mineral density (BMD).bone mineral density (BMD).

There is a positive relation There is a positive relation between maintenance of between maintenance of bone mass and HT with bone mass and HT with estrogen.estrogen.– Decrease rates of wrist, non-Decrease rates of wrist, non-

vertebral, vertebral, and hip vertebral, vertebral, and hip fractures.fractures.

Raloxifene – SERM that Raloxifene – SERM that functions like estrogen functions like estrogen within bone.within bone.

Cardiovascular impactCardiovascular impact

When estrogen binds to its When estrogen binds to its receptors within the liver, it receptors within the liver, it causes cholesterol in the causes cholesterol in the form of lipoproteins to be form of lipoproteins to be synthesized.synthesized.

Cholesterol is in the form of Cholesterol is in the form of LDL or HDL. Estrogen LDL or HDL. Estrogen encourages HDL (good encourages HDL (good cholesterol) to be made cholesterol) to be made and inhibits the formation and inhibits the formation of LDL (bad cholesterol), of LDL (bad cholesterol), and thereby lowers the risk and thereby lowers the risk of cardiovascular disease.of cardiovascular disease.

Cognitive functionCognitive function

Both ER Both ER αα and ER and ER ββ are are found throughout the brain.found throughout the brain.

The expression and the The expression and the activity of these receptors activity of these receptors indicate improvement in indicate improvement in cognitive function.cognitive function.– Data has demonstrated that Data has demonstrated that

estrogen users had a 30% estrogen users had a 30% decrease risk of developing decrease risk of developing Alzheimer’s disease.Alzheimer’s disease.

ConclusionConclusion

Estrogen and Progestin should be used Estrogen and Progestin should be used in conjunction with each other for in conjunction with each other for maximum benefits and minimum risks.maximum benefits and minimum risks.

As technology improves, there will come As technology improves, there will come a time when a harm-benefit analysis of a time when a harm-benefit analysis of estrogen use may be performed to tailor estrogen use may be performed to tailor a treatment plan to individual patients, a treatment plan to individual patients, especially in Hormone Therapy.especially in Hormone Therapy.

Further research is needed to develop Further research is needed to develop better SERMs in order to selectively better SERMs in order to selectively target specific tissue types in cancer target specific tissue types in cancer treatment and Hormone Therapy to treatment and Hormone Therapy to minimize risks.minimize risks.

ReferencesReferences

The Pharmacological Basis of Therapeutics The Pharmacological Basis of Therapeutics by Goodman and by Goodman and GilmanGilman

““Menopause: Developing a rational treatment plan” by Vitiello, Menopause: Developing a rational treatment plan” by Vitiello, et al.et al.

““Perspective: Female Steroid Hormone Action” by Dr. Orla Perspective: Female Steroid Hormone Action” by Dr. Orla ConneelyConneely

““History of Contraception” by Potts and CampbellHistory of Contraception” by Potts and Campbell <http://wikipedia.com><http://wikipedia.com> ““Progesterone vs Progestin” by Dr. Steven HotzeProgesterone vs Progestin” by Dr. Steven Hotze <http://www.cancer.gov><http://www.cancer.gov> ““Advances in HRT: Weight benefits of drospirenone, a 17Advances in HRT: Weight benefits of drospirenone, a 17αα – –

spirolactone-derived progestogenspirolactone-derived progestogen” by Foidart, et al. ” 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 Mechanism of action and clinical effects of antiprogestins on

the non-pregnant uterus” by Spitz, et al.the non-pregnant uterus” by Spitz, et al. <http://www.providence.org><http://www.providence.org>