Steroids: Female Oral Contraceptives and Abortifacients

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Steroids Female Oral Contraceptives and
Abortifacients

• By Judy Garza

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Topics

• Steroid Hormones
• Oral Contraceptives
• Abortifacient
• Ovulation
• Mechanism of Action Oral Contraceptives
• Mechanism of Action Abortifacients
• Male Hormonal Contraceptives
• Side Effects
• Future

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Steroid Hormones

• Steroids that act as hormones.
• Grouped into five groups by the receptor to which
  they bind
• Glucorticoids, mineralcorticoids, androgens,
  estrogens, and progestagens.
• Synthesized from cholesterol in the gonads and
  adrenal glands.
• Carried in the blood going to specific carrier
  proteins (ex. Sex hormone binding globulin or
  corticosteroid binding globulin).

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How do steroid hormones work?

• In cytoplasm they can undergo an enzyme-mediated
  alteration like reduction, hydroxylation, or
  aromatization.
• The steroid binds to the specific receptor.
• The steroid receptor dimerizes
• The steroid-receptor ligand complex binds to
  specific DNA sequences and induces transcription
  of its target genes.

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Oral Contraceptives

• Medications taken by mouth for the purpose of
  birth control.
• They are a class of synthetic steroid hormones
  that suppress the release of follicle-stimulating
  hormone (FSH) and luteinizing hormone (LH) from
  the anterior lobe of the pituitary gland.
• FSH and LH are called gonadotropic hormones and
  they stimulate the release of progesterone and
  estrogen from the ovaries which are responsible
  for modulating the menstrual cycle.

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History of Oral Contraceptives

• 1500 years ago papyrus inscriptions.
• Early 1900s- Ludwig Haberlandt coined the term
  hormonal sterilisation.
• Nov. 1921- Haberlandt presented his work.
• 1927- Haberlandt published
• 1929- Adolf Butenandt isolated the first female
  sex hormone, estrone.
• 1934- Butenandt isolated progesterone from pig
  ovaries.

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History

• 1948- Russel Marker synthesized progesterone
  using wild yam (Dioscorea).
• 1951- Gregory Pincus, Margaret Sanger, et al.
  began researching.
• 1960- 1st pill introduced (Envoid 10mg)
• 1970 Introduction low dose or second generation
  of OCS
• 1980 biphasic or triphasic regimens
• 1990 3rd generation OCS
• (O P has less androgenic activity)

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Abortifacients

• A substance that induces abortion.
• Controversy over the use of them.
• Types
• Herbal (ex. Brewers yeast, vitamin C, wild
  carrot, black cohosh, slippery elm, pennyroyal,
  nutmeg, mugwort, papaya, vervain, etc.)
• Pharmaceutical (Mifepristone and Misoprostol)

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History of Abortifacients

• Ancient Greece the colony of Cyrene had an
  economy based on silphium.
• All throughout history, herbs have been used as a
  means of abortifaceints.
• Modern days surgical methods and medications are
  used.

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Ovulation

• Process in the menstrual cycle where a mature
  ovarian follicle ruptures and discharges an egg
  (ovum).
• Ovulation is triggered by a spike in the amount
  of Follicle-Stimulation Hormone (FSH)and
  Luteinizing Hormone (LH) released from the
  pituitary gland.
• Gonadoptopin releasing hormone (GnRH) stimulates
  the expression of LH and FSH.

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Mechanism of Action Oral Contraceptives

• Progesterone

• Progesterone is the only naturally occurring
  progestagen.
• All have antiestrogenic and antigonadotropic
  properties.
• Differ in their affinity for progesterone
  receptors and side-effects.
• Only synthetic progestagens are used in oral
  contraceptives.

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Mechanism for Oral Contraceptives

• Progesterone (aka Progestagen)

Norethisterone
Norethynodrel
Synthetic Progesterones
Levonorgestrel
Chlormandinone acetate
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Mechanism of Action Oral Contraceptives

• Progestins

• There are two progesterone receptors PR-A and
  PR-B.
• Both have AF-1 and AF-2 transactivation domains.
• Since the ligand-binding domains are identical,
  there is no difference in ligand binding.
• Upon binding to progesterone, the receptors are
  phosphorylated and form dimers that bind with
  high selectivity to progesterone response
  elements (PREs) located on target genes.
• Transcriptional activation occurs after
  recruitment of co-activators like SRC-1 in order
  to have histone acetylase activity.
• This increases the accessibility of general
  transcriptional proteins to the target promoter.

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Mechanism of Action Oral Contraceptives
Gonadropin-releasing hormone

• Progestins
• Progestin-Only Contraceptive

• In the stomach, ovulation is inhibited by
  suppressing function of the hypothalamic-pituitary
  -ovarian axis.
• It then modifies the midcycle surges of
  luteinizing hormone (LH) and follicle-stimulation
  hormone (FSH).
• In the ovaries, hormone production is decreased.
• There are modifications made to the ovaries that
  are unfavorable to implantation and the cervical
  mucus is thickened.
• Also, it inhibits sperm action.

LH, FSH
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Mechanism of Action Oral Contraceptives

• Estrogen

• In oral contraceptives, the estrogens mainly used
  are mestranol and ethinyl estradiol.
• It is produced in the ovaries by FSH and LH.
• Too much estrogen can cause side effects such as
  stroke, deep vein thrombosis, invasive breast
  cancer, heart attack, etc.

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Mechanism of Action Oral Contraceptives

• Estrogen

• Composed of 4 rings.
• The phenolic A ring is the principle structure
  that is responsible for selective, high-affinity
  binding to both receptors.
• Sterodial estrogens arise from androstendione or
  testosterone by aromatization of the A ring.
• Reaction is catalyzed by a cytochrome P450
  monooxygenase enzyme complex that uses NADPH and
  oxygen as co-substrates.

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Mechanism of Action Oral Contraceptives

• Estrogen

• Act primarily on the pituitary to control the
  amplitude of gonadtropic pulses and contribute to
  the amplitude of GnRH pulses secreted by the
  hypothalamus.
• They also inhibit gonadotropin (LH and FSH)
  release during the menstrual cycle, but then they
  have a mid-cycle stimulatory action that
  increases the amount released causing LH to surge.

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Mechanism of Action Oral Contraceptives

• Estrogen

• The hormone enters the cell and binds to an
  estrogen receptor (ESR 1, ESR 2).
• Binding causes a conformational change and causes
  receptor to dimerize which increases the affinity
  and rate of receptor binding to DNA.
• ER dimer binds to estrogen response elements
  located in the promoter region of target genes
  where it then can regulate many of the same
  target genes.

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Mechanism of Action Oral Contraceptives

• Estrogen Progestins
• (aka Combination Oral Contraceptives)

• Progestins bind to albumin and sex hormone
  binding globulin in plasma then diffuse into cell
  cytoplasm
• Estrogen is lipid soluble and thus diffuses.
• Once in the cell, they regulate the transcription
  of specific genes in the uterus.
• Actions of hormones are mediated by their hormone
  receptors which are nuclear transpcription
  factors whose transcriptional regulartory
  activity is mediated by the binding of the
  specific steroid to these molecules.
• Once the receptors bind hormone, they bind to
  cis-acting sequences in the promoter region of
  responsive genes and regulate transcription of
  these genes.

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Mechanism of Action Oral Contraceptives

• Estrogen Progestin (aka Combination Oral
  Contraceptives)

• The progestin negative feedback decreases the
  frequency of GnRH released.
• This decreases the release of FSH and LH which
  inhibit follicle development.
• Estradial levels do not increase (no positive
  feedback).
• In addition it decreases the amount of and
  viscosity of the cervical mucus, inhibiting sperm
  penetration.
• Estrogen also contributes to decreasing the
  amount of FSH produced by negative feedback on
  the anterior pituitary.
• No ovulation occurs as a result

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Mechanism of Action Oral Contraceptives

• Estrogen Progestin (aka Combination Oral
  Contraceptives)

• Monophasic
• Same amount of estrogen and progestin in each
  active pill.
• Classified by estrogen level
• Low dose (20 mcg)
• Regular dose (30-35 mcg)
• High dose (50 mcg)
• Biphasic
• Alter the level of hormones once during the
  menstrual cycle.
• Same amount of estrogen but halfway through the
  cycle, progestin is increased.
• Triphasic
• 3 different doses of hormones.
• Depending on brand, estrogen may increase.

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Types of Oral Contraceptives

• Progesterone-Only
• Evonid
• Minipill
• Monophasic
• Yasmin
• Biphasic
• Necon
• Triphasic
• Cyclessa (100 ug, 125 ug, or 150 ug desogesterl)
• Ortho Tri-Cyclen Lo
• Tri-Norinyl

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Mechanism of Action Abortifacients

• Mifepristone (aka RU-486)
• It is a competitive receptor antagonist in the
  presence of progesterone at the progesterone
  receptor.
• It causes the decidual degeneration which leads
  to trophoblast detachment.
• Results in decreased production of Human chronic
  gonadotropin (hCG), which causes decreased
  production of progesterone by the corpus luteum.
  
• Since pregnancy is dependant on progesterone
  production by the corpus lutenum, pregnancy is
  terminated.
• In addition it increases prostagladin release
  from the uterine lining, increasing uterine
  contractions and enhances the uterus sensitivity
  to prostagladin.

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Mechanism of Action Abortifacient

• Methotrexate
• Blocks enzyme necessary for DNA synthesis, which
  inhibits the growth of placental trophoblastic
  cells.

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Mechanism of Action Abortifacient

• Misoprostol
• Synthetic protaglandin E1 analogue.
• Used in combination with Mifepristone and
  Methotrexate.
• Softens and dilates the cervix.
• Binds to myometrial cells to cause uterine
  contractions which cause expulsion of the embryo.

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Abortifacients

• Plan-B
• Consists of two doses of the minipill (.75 mg
  levonorgestrel per pill) separated by 12 hours.
• Preven (Yuzpe)
• A two 2-pill doses of a high-dose oral
  contraceptive (.25 mg of levonorgestrel and .05
  mg of ethinyl estradiol per pill) separated by 12
  hours.

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Other Types of Contraceptives

• Vaginal rings
• Nuvaring
• Transdermal
• Contraceptive patches
• Nestorone gel
• Intrauterine
• Progestasert
• Mirena
• Intramuscular
• Gravibinon
• Subcutaneous
• Norplant

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Male Contraceptives

• Still in clinical trials.
• Stopping the secretion of a mans reproductive
  hormones in the brain and the testes to reduce or
  block sperm is the ultimate goal.

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Side Effects

• Blood clots
• Heart attacks
• Stroke
• Cancer
• Depression
• Nausea
• Dizziness
• Stomach upset
• Headache

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Future

• Looking at reducing the risks involved with
  taking the pill.
• Using natural products.
• Vaccines

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Refrences

• Matthiesson, Kati L. and McLachlan Robert. Male
  hormonal contraceptionconcept in sight? Human
  Reproduction Update, Vol.12, No.4 pp. 463482,
  2006
• Ferro, Valerie and Mann, Jamie. Recent
  Developments in Female Hormonal Contraception.
  Current Womens Health Reviews, 2005, 1, 105-118
• Benagiano, Giuseppe, Bastianelli, Carlo and
  Farris Manuela. Contraception Today. ANNALS NEW
  YORK ACADEMY OF SCIENCES
• Orme, M.LE. The Clinical Pharmacology of Oral
  Contraceptive Steroids. Br. J. clin. Pharmac.
  (1982), 14, 31-42
• Mears, Eleanor. Clinical Trials of Oral
  Contraceptives. British Medical Journal. Nov. 4.
  1961
• http//www.contraceptiononline.org/contrareport/ar
  ticle01.cfm?art160
• http//www.nytimes.com/learning/general/onthisday/
  bday/0409.html
• http//www.djerassi.com/CEcontraceptives/index.htm
  l