2. Female Sex Hormones And Antagonists:
Natural Estrogens And Progestins
• Biologically important natural estrogens and progestins include
estradiol, estrone, estriol, and progesterone.
• Estradiol-17β:
– the most potent estrogen that is found naturally in women.
• Progesterone:
– the most important naturally occurring progestin.
• The ovary:
– The major site of estrogen and progestin biosynthesis in non
pregnant premenopausal women.
• The fetoplacental unit:
– the major source of estrogens and progestins in pregnant
women.
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3. Natural Estrogens And Progestins cont…
• In postmenopausal women,
– ovarian steroid synthesis declines.
– liver, kidney, brain, adipose tissue, and skeletal muscle
accounts for all estrogen produced
• The naturally occurring estrogens and progestins are not
orally active.
– rapidly metabolically inactivated.
– Their plasma half-life measured in minutes.
– primarily excreted in the urine.
• The major site of estrogen and progestin metabolism is the
liver.
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4. Mechanisms of Action
• High-affinity estrogen and progestin receptors are found in
target tissues.
• Receptor binding by estrogens and progestins
– activate a classic pathway of steroid hormone gene
transcription.
• Hypothalamic-Pituitary–Reproduction Axis
– Regulates sex hormone synthesis.
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5. Actions of Estrogens and Progestins in Females:
I. The Menstrual Cycle
• The female menstrual cycle:
– governed by the cycling of hormones with an approximate
periodicity of 28 days (normal range, 24–35 days).
• Cycle begins at the onset of puberty and continues
uninterrupted (with the exception of pregnancy) until
menopause.
• Cycle day 1,
– arbitrarily defined as the first day of menstruation.
• Ovulation occurs at the midportion (about day 14) of each
cycle.
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6. The Menstrual Cycle cont…
• Follicular or proliferative phase:
– the portion of the menstrual cycle before ovulation;
– the developing ovarian follicle produces most of the
gonadal hormones, which stimulate cellular proliferation
of the endometrium.
• Luteal or secretory phase:
– The second half of the menstrual cycle.
– The corpus luteum produces progesterone, and the
endometrium becomes secretory rather than proliferative.
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7. Follicular or proliferative phase
• As the dominant follicle continues to grow,
– it secretes high, sustained levels of estrogen.
• The combination of high estrogen levels and the rapid rate of
increase of estrogen levels,
– Causes a brief positive feedback effect, stimulating release
of LH and FSH.
– The mechanism is still not completely understood.
• The resulting midcycle surge of LH and FSH
– Stimulates the dominant follicle to swell and to increase
the activity of its proteolytic enzymes.
• Approximately 40 hours after the onset of the LH surge,
– the follicle ruptures and ovulation occurs.
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8. Luteal or secretory phase
• If the oocyte becomes fertilized in the fallopian tube, it
reaches the uterus approximately 4 days after ovulation and
implants into the endometrium approximately 5–6 days after
ovulation.
• The cellular remains of the ruptured ovarian follicle become
the corpus luteum.
– secrete estrogen and progesterone.
• Progesterone in the second half of the menstrual cycle
– causes the endometrium to switch from a proliferative to
a secretory state.
• The endometrium begins synthesizing proteins necessary for
implantation of a fertilized egg.
• The blood supply to the endometrium also increases to
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provide increased nutrients if pregnancy ensues.
9. Luteal or secretory phase cont…
• The corpus luteum has a lifespan of approximately 14 days.
• If fertilization and implantation do not occur within 14
days of ovulation,
– corpus luteum becomes atretic and ceases its production
of estrogen and progesterone,
– the endometrial lining sheds and menstruation begins.
• In the absence of estrogen and progesterone,
– inhibition of gonadotrophs is removed, and
– production of FSH and LH increases.
– beginning of another menstrual cycle.
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10. The Menstrual Cycle cont…
• If fertilization and implantation occur,
– Blastocyst secrete human Chorionic Gonadotropin (hCG).
• hCG stimulates the corpus luteum to remain viable and
continue secreting progesterone.
• hCG,
– One of the first proteins produced by the embryo that is
unique to pregnancy,
– Pregnancy tests assay for the presence of hCG.
– Its production decreases after 10-12 weeks of pregnancy,
when the placenta begins to secrete progesterone
autonomously.
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13. II. Growth and Development
• Estrogens:
– cause the growth of the uterus, fallopian tubes, and vagina.
– responsible for the expression of female secondary sex
characteristics during puberty.
– stimulate proliferation of the ductal epithelial cells in
breast tissue.
• Progesterone mediates lobuloalveolar development at the
ends of these mammary ducts.
• Estrogens can stimulate the release of growth hormone.
– contribute to the growth spurt during puberty.
• Closure of the bone epiphyses signaling the end of long bone
growth is also estrogen mediated.
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14. II. Growth and Development cont…
• Bone remodeling occurs throughout adult life.
• Osteoblasts,
– bone cells that are responsible for increasing bone mass.
• Osteoclasts,
– bone cells causing bone loss.
• Normal bone remodeling takes place when there is a balance
between osteoblast and osteoclast activities.
• Estrogens maintain bone mass by inhibiting bone resorption by
the osteoclasts.
• In postmenopausal women, declining estrogen levels,
– give rise to a net increase in osteoclast activity.
– loss of bone mass
• Osteoporosis.
• Also, progestins antagonize loss of bone.
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15. III. Other Actions of Estrogens and Progestins
• High circulating levels of estrogen can cause mild glucose
intolerance.
• Estrogens increase the synthesis of many liver proteins, including:
– transferrin, Sex Hormone Binding Globulin, corticosteroidbinding globulin, and proteins involved in blood clotting
(Increases blood coagulability).
• Estrogens lower serum cholesterol levels by stimulating the
formation of HDL and reducing LDL.
• They also facilitate the loss of intravascular fluid into the
extracellular space,
– Producing edema.
– The resulting decrease in plasma volume causes a
compensatory retention of sodium and water by the kidney.
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16. Synthetic Estrogens And Progesterone
• Long-acting semisynthetic estrogens and progestins contain
esterified lipophilic substituents.
• Esterification of steroids prolongs their release from depot
injection sites.
• Medroxyprogesterone acetate (Provera, Depo-Provera),
– a widely used long-acting synthetic progestin.
• Synthetic steroid hormones retain the common steroid
nucleus, but they may contain novel substituents that affect
their pharmacological activity.
• The two most widely used synthetic steroid estrogens,
– ethinyl estradiol and mestranol,
• found in oral contraceptives.
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17. Synthetic Estrogens and cont…
• Synthetic steroid hormones:
– have better oral absorption properties
– extended biological half-lives than the natural estrogens.
• Norgestrel, Norethindrone, norethindrone acetate,
Medroxyprogesterone, Megestrol acetate
– Are synthetic progestin analogues
• Norethindrone acetate is very readily cleaved to yield
norethindrone.
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18. Clinical Uses of Estrogens and Progestins and analogues
•
•
•
•
•
•
Contraception
Hormone replacement therapy.
Osteoporosis,
Breast cancer,
Endometrial cancer,
Infertility.
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19. Hormonal Contraception
• Progestins, alone or in combination with estrogens, can be
used to prevent conception.
• Oral contraceptives are among the most effective forms of
birth control.
• Two types of preparations are used for oral contraception:
– (1) combinations of estrogens and progestins (COCs) and
– (2) Progestin-Only Contraception.
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20. 1. Combinations of estrogens and progestins
• The most common & highly effective for contraception.
• Designed to more closely simulate estrogen-to-progestin
ratios that occur physiologically during the menstrual cycle.
• Levonorgestrel and norethindrone
– the most potent synthetic progestins in oral contraceptive
preparations.
• Users take a tablet daily that contains both an estrogen and a
progestin for 20 to 21 days of the menstrual cycle and then
nothing or a placebo for the remainder of the cycle or the next
7 to 8 days.
• Withdrawal bleeding occurs 2 to 3 days after discontinuation
of this regimen.
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21. Mechanism of action
• Combination estrogen-progestin contraception:
– suppresses GnRH, LH, and FSH secretion and follicular
development,
• inhibiting ovulation.
• Midcycle surge of FSH and LH blocked.
• Co-administration of estrogen and progestin may also inhibit
pregnancy by a number of secondary mechanisms, including:
– alterations in tubal peristalsis, endometrial receptivity, and
cervical mucus secretions.
• Inhibit the proper transport of both egg and sperm, even if
ovulation were to occur.
• These mechanisms explain the >95% efficacy of COCs.
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22. 1. Combinations of estrogens and cont…
• Classical regimens of combination oral contraceptive tablets
consist of 21 days of drugs followed by 7days of a placebo
pill.
• The 7-day placebo period removes exogenous hormone
stimulation, causing the endometrium to slough and resulting
in withdrawal bleeding.
• The 21-7 cycle formulation was meant to simulate a 28-day
cycle, but is relatively arbitrary.
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23. 1. Combinations of estrogens and cont…
• By combining pill packs, “long cycles” of 42 active hormone
pills followed by 7 days off hormone pills, or 63 active
hormone pills followed by 7 days off hormone pills can easily
be prescribed.
• “Long cycle” regimens reduce the frequency of menstrual
bleeding but may increase the frequency of irregular,
unscheduled bleeding.
• An even longer cycle formulation in which the drug
combination is administered for 84 days followed by 7 days
of placebo.
– reduces to four the total number of menstrual cycles each
year.
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24. Adverse Effects of COCs
•
•
•
•
•
•
•
GIT disturbances, Headache, Breakthrough bleeding,
Oedema because of water and salt retention,
Increase in pigmentation,
Thromboembolism,
Mental depression and change in libido (few cases).
Ocular reactions due to optic neuritis and retinal thrombosis.
Metabolic disorders:
– increase of serum triglycerides and total phospholipids
and decrease of glucose tolerance.
• Interference with lactation.
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26. 2. Progestin-Only Contraception
• Not extensively used because of:
– an increased incidence of certain side effects and
– slightly decreased contraceptive activity.
• It can be used in situations where estrogen may be
contraindicated.
• The undesirable side effects associated with progestin-only
contraceptives are;
– irregular bleeding episodes,
– headache, weight gain, and mood changes.
• Norgestrel and Norethindrone.
– Commonly used two progestin-only oral contraceptives.
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27. 2. Progestin-Only Contraception cont…
• Prevents ovulation 70-80% of the time,
– probably because progestins alter the frequency of GnHR
pulsing and decrease anterior pituitary gland
responsiveness to GnHR.
• Despite the relatively high frequency of ovulation,
effectiveness of this form of contraception more than 90%
– suggesting that secondary mechanisms- such as
• alterations in cervical mucus,
• endometrial receptivity, and tubal peristalsis-are also at
work.
• progesterone inhibits endometrial proliferation and promotes
endometrial secretion,
– an egg is unable to implant to the endometrium.
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28. 2. Progestin-only contraception cont…
• Patients taking these drugs continuously do not menstruate,
– but breakthrough spotting and irregular, light menstrual
periods commonly occur during the first year of
administration.
• Are also available as injectables and implants.
• Medroxyprogesterone acetate (formulated as 104 mg for
Sc. 150 mg for IM injection) can be given parenterally every
3 months,
– Effective for women who have difficulty remembering to
take a daily pill.
• Progestin-only contraceptive devices are also used.
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29. Progestin-only contraceptive devices
• The Norplant System for contraception
– consists of a series of levonorgestrel-filled pliable plastic
tubes that are implanted subcutaneously on the inside of
the upper arm by a physician.
– one set of six tubes can remain effective for up to 5 years,
the contraceptive effects are readily reversible with
removal of the implant.
• Adverse effects:
– similar to those seen with other progestin-only
contraceptives; however, accidental pregnancy is less
frequent.
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30. Progestin-only contraceptive devices cont…
• Mirena
– a relatively new intrauterine contraceptive device that
releases levonorgestrel into the uterine cavity for 5 years.
– Its use is associated with fewer systemic progestin side
effects and
– is at least as effective as Norplant.
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