Steroids: Estrogen and Progestin

Steroids: Estrogen and Progestin

Jennifer KettelProfessor John Buynak

CHEM 5398March 27, 2007

Jennifer KettelProfessor John Buynak

CHEM 5398March 27, 2007

IntroductionIntroduction• Estrogens• Progestins• Hormone Contraceptives

– Combination Contraceptives– Progestin-Only Contraceptives– Emergency Contraceptives

• Estrogens• Progestins• Hormone Contraceptives

– Combination Contraceptives– Progestin-Only Contraceptives– Emergency Contraceptives

Estrogens and ProgestinsEstrogens and Progestins• Estrogens and progestins are hormones that produce many

physiological actions• In women,

– Developmental effects (estrogens are largely responsible for pubertal changes in girls and secondary sexual characteristics)

– Neuroendocrine actions involved in: Control of ovulation and the preparation of the reproductive tract for fertilization and implantation

– Major Actions on: Minerals, Carbohydrates, Proteins, and Lipid Metabolism

• In men, effects:– Bone– Spermatogenesis– Behavior

• Estrogens and progestins are hormones that produce many physiological actions

• In women,– Developmental effects (estrogens are largely responsible for

pubertal changes in girls and secondary sexual characteristics)– Neuroendocrine actions involved in: Control of ovulation and the

preparation of the reproductive tract for fertilization and implantation

– Major Actions on: Minerals, Carbohydrates, Proteins, and Lipid Metabolism

• In men, effects:– Bone– Spermatogenesis– Behavior

EstrogensEstrogens• A group of steroid hormones that readily diffuse across

the cell membrane• Inside the cell, they interact with estrogen receptors

• A group of steroid hormones that readily diffuse across the cell membrane

• Inside the cell, they interact with estrogen receptors

Estriol Estradiol Estrone

AA A

D D D

Estrogen SynthesisEstrogen Synthesis• Estrogen is produced primarily by developing follicles in the

ovaries, the corpus luteum, and the placenta• Follicle-stimulating hormone (FSH) and luteinizing hormone

(LH) stimulate the production of estrogen in the ovaries• Some estrogens are also produced in smaller amounts by

other tissues such as the liver, adrenal glands, and the breasts

• The ovaries are the principal source of circulating estrogen in premenopausal women, with estrodiol being the main secretory product

• In postmenopausal women, the principal circulating estrogen estrone, which is synthesized from dehydroepiandrosterone and secreted by the adrenals

• Estrogen is produced primarily by developing follicles in the ovaries, the corpus luteum, and the placenta

• Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) stimulate the production of estrogen in the ovaries

• Some estrogens are also produced in smaller amounts by other tissues such as the liver, adrenal glands, and the breasts

• The ovaries are the principal source of circulating estrogen in premenopausal women, with estrodiol being the main secretory product

• In postmenopausal women, the principal circulating estrogen estrone, which is synthesized from dehydroepiandrosterone and secreted by the adrenals

Estrogen SynthesisEstrogen Synthesis• The most potent naturally occurring estrogen in humans for

both the Estrogen Receptor alpha- and beta-mediated actions is 17beta-estradiol, followed by estrone and estriol

• Each estrogen contains a phenolic A ring with a hydroxyl group at carbon 3 and a beta-OH or ketone in position 17 of ring D

• The phenolic A ring is the principal structural feature responsible for selective, high-affinity binding to both receptors

• Synthesis of estrogen begins from the synthesis of androstenedione from cholesterol

• Androstenedione crosses the basal membrane into surrounding granulosa cells, where its converted to estrone or estradiol wither immediately or through testosterone

• The conversion is catalyzed by aromatase

• The most potent naturally occurring estrogen in humans for both the Estrogen Receptor alpha- and beta-mediated actions is 17beta-estradiol, followed by estrone and estriol

• Each estrogen contains a phenolic A ring with a hydroxyl group at carbon 3 and a beta-OH or ketone in position 17 of ring D

• The phenolic A ring is the principal structural feature responsible for selective, high-affinity binding to both receptors

• Synthesis of estrogen begins from the synthesis of androstenedione from cholesterol

• Androstenedione crosses the basal membrane into surrounding granulosa cells, where its converted to estrone or estradiol wither immediately or through testosterone

• The conversion is catalyzed by aromatase

Biosynthetic PathwayBiosynthetic Pathway

This figure shows the major metabolic intermediates in the usual synthesis of estrogen, starting with cholesterol, proceeding to pregnenolone, an androgen, and then estrogen.

http://www.chemistryexplained.com/Di-Fa/Estrogen.html

Estrogen ReceptorsEstrogen Receptors• Estrogens exert their effects by interaction with receptors that are

members of the super family of nuclear receptors• The two estrogen receptor (ER) genes are located on separate

chromosomes: ESR1 encodes ER-alpha and ESR2 encodes ER-beta • Both ERs are estrogen-dependent nuclear transcription factors that

have different tissue distributions and transcriptional regulatory effects on target genes

• Both ERs are ligand-activated transcription factors that increase or decrease the transcription of target genes

• After entering the cell by passive diffusion through the plasma membrane, the hormone binds to an ER in the nucleus

• In the nucleus, the ER is present as an inactive monomer bound to heat-shock proteins, and upon binding estrogen, a change in ER confirmation dissociates the heat-shock proteins and causes receptor dimerization, which increases the affinity and the rate of receptor binding to DNA

• Estrogens exert their effects by interaction with receptors that are members of the super family of nuclear receptors

• The two estrogen receptor (ER) genes are located on separate chromosomes: ESR1 encodes ER-alpha and ESR2 encodes ER-beta

• Both ERs are estrogen-dependent nuclear transcription factors that have different tissue distributions and transcriptional regulatory effects on target genes

• Both ERs are ligand-activated transcription factors that increase or decrease the transcription of target genes

• After entering the cell by passive diffusion through the plasma membrane, the hormone binds to an ER in the nucleus

• In the nucleus, the ER is present as an inactive monomer bound to heat-shock proteins, and upon binding estrogen, a change in ER confirmation dissociates the heat-shock proteins and causes receptor dimerization, which increases the affinity and the rate of receptor binding to DNA

Anti-estrogens and SERMsAnti-estrogens and SERMs

• Anti-estrogens– Pure antagonists– Clomiphene is for

treatment of infertility in anovulatory women

– Fulvestrant is used for the treatment of breast cancer

• Anti-estrogens– Pure antagonists– Clomiphene is for

treatment of infertility in anovulatory women

– Fulvestrant is used for the treatment of breast cancer

• Selective Estrogen Receptor Modulators (SERMs)– Compounds with

tissue-selective actions– The goal of these drugs

is to produce beneficial estrogenic actions in certain tissues (ex. Brain, bone, liver) during postmenopausal hormone therapy

– Tamoxifen, Raloxifen, Toremifine

• Selective Estrogen Receptor Modulators (SERMs)– Compounds with

tissue-selective actions– The goal of these drugs

is to produce beneficial estrogenic actions in certain tissues (ex. Brain, bone, liver) during postmenopausal hormone therapy

– Tamoxifen, Raloxifen, Toremifine

ProgestinsProgestins• Progestins include the naturally occurring hormone

progesterone, 17-acetoxyprogesterone derivatives in the pregnane series, 19-nortestosterone derivatives (estranges), and norgestrel and related compounds in the gonane series

• Progestins include the naturally occurring hormone progesterone, 17-acetoxyprogesterone derivatives in the pregnane series, 19-nortestosterone derivatives (estranges), and norgestrel and related compounds in the gonane series

progesterone 17-acetoxyprogesterone 19-nortestosterone

norgestrellevonorgestrel

Physcical Actions of ProgesteronePhyscical Actions of Progesterone

• In the reproductive tract, progesterone decreases estrogen-driven endometrial proliferation and leads to the development of a secretory endometrium

• The abrupt decline in progesterone at the end of the cycle is the main determinant of the onset of menstruation

• Progesterone is very important for the maintenance of pregnancy

• It suppresses menstruation and uterine contractility

• In the reproductive tract, progesterone decreases estrogen-driven endometrial proliferation and leads to the development of a secretory endometrium

• The abrupt decline in progesterone at the end of the cycle is the main determinant of the onset of menstruation

• Progesterone is very important for the maintenance of pregnancy

• It suppresses menstruation and uterine contractility

The Progestin ReceptorThe Progestin Receptor•Unlike the ER receptor, which requires a phenolic ring for binding, the PR favors a non-phenolic ring structure•There is a single gene that encodes two isoforms of the progesterone receptor (PR): PR-A and PR-B•Since the ligand-binding domains of the two PR isoforms are identical, there is no difference in ligand binding•However, the biological activities of PR-A and PR-B are distinct and depend on the target gene in question

•PR-B mediates the stimulatory activities of progesterone•PR-A strongly inhibits this action of PR-B

•Upon binding progesterone, the heat-shock proteins dissociate, and the receptors are phosphorylated and subsequently form dimers (homo- and hetero-) that bind with high selectivity to progesterone response elements located on target genes

•Unlike the ER receptor, which requires a phenolic ring for binding, the PR favors a non-phenolic ring structure•There is a single gene that encodes two isoforms of the progesterone receptor (PR): PR-A and PR-B•Since the ligand-binding domains of the two PR isoforms are identical, there is no difference in ligand binding•However, the biological activities of PR-A and PR-B are distinct and depend on the target gene in question

•PR-B mediates the stimulatory activities of progesterone•PR-A strongly inhibits this action of PR-B

•Upon binding progesterone, the heat-shock proteins dissociate, and the receptors are phosphorylated and subsequently form dimers (homo- and hetero-) that bind with high selectivity to progesterone response elements located on target genes

Anti-progestinsAnti-progestins• Anti-progestin, first discovered in

1981, is mifepristone, used to terminate pregnancy

• In the presence of progesterone, mifepristone acts as a competitive receptor antagonist for both progesterone receptors

• When administered in the early stages of pregnancy, mifepristone causes decidual breakdown by blocking uterine progesterone receptors, which leads to detachment of the blastocyst, decreasing hCG production

• Anti-progestin, first discovered in 1981, is mifepristone, used to terminate pregnancy

• In the presence of progesterone, mifepristone acts as a competitive receptor antagonist for both progesterone receptors

• When administered in the early stages of pregnancy, mifepristone causes decidual breakdown by blocking uterine progesterone receptors, which leads to detachment of the blastocyst, decreasing hCG production

Mifepristone

Hormonal Contraceptives

Hormonal Contraceptives

Brief HistoryBrief History

• At the beginning of the 20th century, European scientists (Beard, Prenant, and Loeb) developed the concept that secretions of the corpus luteum suppressed ovulation during pregnancy

• By the 1930s, scientists had isolated and determined the structure of the steroid hormones and found that high doses of androgens, estrogens or progesterone inhibited ovulation

• At the beginning of the 20th century, European scientists (Beard, Prenant, and Loeb) developed the concept that secretions of the corpus luteum suppressed ovulation during pregnancy

• By the 1930s, scientists had isolated and determined the structure of the steroid hormones and found that high doses of androgens, estrogens or progesterone inhibited ovulation

History cont.History cont.

• In June 1957, the FDA approved Enovid 10mg for menstrual disorders

• Later, in May 1960, the FDA approved Enovid for contraceptive use

• Although the FDA approved this drug for contraceptive use, it was not available to married women in all states until 1965 and unmarried women in all states until 1975

• In June 1957, the FDA approved Enovid 10mg for menstrual disorders

• Later, in May 1960, the FDA approved Enovid for contraceptive use

• Although the FDA approved this drug for contraceptive use, it was not available to married women in all states until 1965 and unmarried women in all states until 1975

Types of Hormonal

Contraceptives

Types of Hormonal

Contraceptives

Combination ContraceptivesCombination Contraceptives

• This type is the most frequently used in the United States, which contain both an estrogen and a progestin

• The theoretical efficacy is 99.9%• Ethinyl estradiol (a synthetic estrogen) and

mestranol are the estrogens most frequently used

• Levonorgestrel is the most common progestin used worldwide

• Currently, this type of contraceptives have lowered doses of estrogen (“low-dose”)

• This type is the most frequently used in the United States, which contain both an estrogen and a progestin

• The theoretical efficacy is 99.9%• Ethinyl estradiol (a synthetic estrogen) and

mestranol are the estrogens most frequently used

• Levonorgestrel is the most common progestin used worldwide

• Currently, this type of contraceptives have lowered doses of estrogen (“low-dose”)

Forms of Combination ContraceptivesForms of Combination Contraceptives• The Pill• The Patch • Vaginal Ring

• The Pill• The Patch • Vaginal Ring

Combination ContraceptivesCombination Contraceptives• Mechanism of Action

– Act by preventing ovulation– Measurements of plasma hormone levels

indicate that LH and FSH levels are suppressed– The mid-cycle surge of LH is absent– Endogenous steroid levels are diminished– Thus, ovulation does not occur– The multiple actions of estrogens and progestins

on the hypothalamic-pituitary-ovarian axis during the menstrual cycle and the efficacy of these agents all contribute to the blockade of ovulation

• Mechanism of Action– Act by preventing ovulation– Measurements of plasma hormone levels

indicate that LH and FSH levels are suppressed– The mid-cycle surge of LH is absent– Endogenous steroid levels are diminished– Thus, ovulation does not occur– The multiple actions of estrogens and progestins

on the hypothalamic-pituitary-ovarian axis during the menstrual cycle and the efficacy of these agents all contribute to the blockade of ovulation

Progestin-Only ContraceptivesProgestin-Only Contraceptives• They contain progestins

only, termed “mini pills”• Slightly less effective, with

99% efficacy• Forms

– Pills– Injectables

• Their effectiveness is thought to be due largely to a thickening of cervical mucus, which decreases sperm penetration and impairs implantation

• They contain progestins only, termed “mini pills”

• Slightly less effective, with 99% efficacy

• Forms– Pills– Injectables

• Their effectiveness is thought to be due largely to a thickening of cervical mucus, which decreases sperm penetration and impairs implantation

Emergency ContraceptivesEmergency Contraceptives• The FDA has approved two preparations• PLAN-B includes 2 doses of levonorgestrel separated by 12

hours (progestin-only)• PREVEN is a 2 pill dose of a high-dose oral contraceptive

(levonorgestrel and ethinyl estradiol) separated by 12 hours

• The first dose of these drugs should be taken 72 hours after intercourse

• The FDA has approved two preparations• PLAN-B includes 2 doses of levonorgestrel separated by 12

hours (progestin-only)• PREVEN is a 2 pill dose of a high-dose oral contraceptive

(levonorgestrel and ethinyl estradiol) separated by 12 hours

• The first dose of these drugs should be taken 72 hours after intercourse

PLAN B

Emergency ContraceptivesEmergency Contraceptives• Multiple mechanisms are likely to contribute to the efficacy of

these agents, however, the exact mechanism is unknown• These mechanisms include:

– Ovulation is inhibited or delayed, alterations in endometrial receptivity for implantation

– Interference with functions of the corpus luteum that maintain pregnancy

– Production of a cervical mucus that decreases sperm penetration

– Alterations in tubular transport of sperm, egg, or embryo– Effects on fertilization

• Emergency contraceptives do not interrupt pregnancy after implantation

• Multiple mechanisms are likely to contribute to the efficacy of these agents, however, the exact mechanism is unknown

• These mechanisms include:– Ovulation is inhibited or delayed, alterations in endometrial

receptivity for implantation– Interference with functions of the corpus luteum that

maintain pregnancy– Production of a cervical mucus that decreases sperm

penetration– Alterations in tubular transport of sperm, egg, or embryo– Effects on fertilization

• Emergency contraceptives do not interrupt pregnancy after implantation

Side EffectsSide Effects

• Many side effects were found to be dose dependent, hence the development of the current low-dose preparations

• Side effects include:– Cardiovascular effects (hypertension, myocardial

infarction, hemorrhagic stroke, venous thrombosis)– Breast, Hepatocellular, and Cervical Cancers– Endocrine and Metabolic effects

• Currently, its found that the low-dose preparations pose minimal health risks in women who have no predisposing risk factors

• Many side effects were found to be dose dependent, hence the development of the current low-dose preparations

• Side effects include:– Cardiovascular effects (hypertension, myocardial

infarction, hemorrhagic stroke, venous thrombosis)– Breast, Hepatocellular, and Cervical Cancers– Endocrine and Metabolic effects

• Currently, its found that the low-dose preparations pose minimal health risks in women who have no predisposing risk factors

Male Birth Control?Male Birth Control?

• Current research and development is in various stages, some which include– A male version of “the pill”– A male hormonal contraceptive

implanted under the skin– A drug which interferes with the

maturation of sperm in the epididymis– Plugs that block the vas deferens

• Current research and development is in various stages, some which include– A male version of “the pill”– A male hormonal contraceptive

implanted under the skin– A drug which interferes with the

maturation of sperm in the epididymis– Plugs that block the vas deferens