PROGESTOGENS

Pr. Abd El-Aty

Pharmacology Department
Ataturk University
 Preface
• Progesterone
– A natural progestogen
– Produced in response to luteinizing hormone (LH)
• In females
– Secreted by the CL (during the second half of the
menstrual cycle)
– By the placenta
• In males
– Secreted by the testes
• It is also synthesized by the adrenal cortex in both sexes
Cont’d
Cont’d
Cont’d
Cont’d
 Mechanism of action
• In females
– It inhibits the production of gonadotropin
and, therefore, prevent further ovulation
– It promotes the development of a
secretory endometrium to accommodate
implantation of a newly forming embryo
– If conception takes place
• It reduces uterine contractions
– If conception does not take place
• The release ceases abruptly from CL
Cont’d
 Therapeutic uses of progestogens
• Contraception
– Itself is not used widely as a contraceptive therapy
– Because of its rapid metabolism
– Resulting in low bioavailability
– Often used in combination with estrogens
• Synthetic progestogens (progestin)
– More stable to first-pass metabolism
– Allowing lower doses when administered orally
– Medroxyprogesterone is an injectable and/or oral contraceptive
• Treatment of hormone deficiency
• Dysfunctional uterine bleeding
• Dysmenorrhea
 Pharmacokinetics
• A micronized preparation
– Rapidly absorbed after oral administration
– It has a short half-life in the plasma
– It is completely metabolized by the liver
– The glucuronidated metabolite is excreted primarily by the
kidney
• Synthetic progestins
– Less rapidly metabolized
– Oral medroxyprogesterone acetate has a half-life of 30 days
– When injected IM or SC, it has a half-life of about 40 to 50 days
• The other progestins have half-lives of 1 to 3 days, allowing for
once-daily dosing
Adverse effects
 Antiprogestin

• Mifepristone (200 mg - also designated as RU-486)

– A progesterone antagonist with partial agonist activity
– It causes abortion when given at early stage of pregnancy
(49 days)
• It is often combined with the prostaglandin analog
misoprostol (800 mcg - administered orally or intravaginally)
– To induce uterine contractions (labor)
– They are given simultaneously
• The major adverse effects are
– Significant uterine bleeding
– Possibility of an incomplete abortion
Cont’d
SPRMs
CONTRACEPTIVES
 Cont’d
• Interference with ovulation
– The most common pharmacologic intervention for prevention of
pregnancy
• Major classes of contraceptives
• 1. Combination oral contraceptives (COCP)
– Products containing a constant dose of estrogen and progestin
(Monophasic combination pills)
– The most common type of oral contraceptives
– Given over 21 to 24 days
– Followed by 4 to 7 days of placebo
– A total regimen of 28 days
– Withdrawal bleeding occurs during the hormone-free (placebo)
interval
 How it work?
• Preventing the release of
mature egg or stopping the
process of ovulation
altogether
• Making cervical mucus
thicker to restrict the entry of
sperms
• Making uterine lining thinner
to prevent implantation
Biphasic pills
 Cont’d
• Triphasic oral contraceptive
products
– Mimic the natural female cycle
– Most contain a constant dose
of estrogen with increasing
doses of progestin
– Given over three successive 7-
day periods
• Four-phasic oral contraceptive
– A combination of estradiol
valerate and dienogest
Triphasic oral contraceptive products
Cont’d
 2. Transdermal patch
• It contains ethinyl estradiol and the progestin norelgestromin
• One patch is applied each week for 3 weeks
– To the abdomen, upper torso, or buttock
• No patch is worn during the 4th week
• Withdrawal bleeding occurs
• Has efficacy comparable to that of the oral contraceptives
• Less effective in women weighing > 90 kg
• Total estrogen exposure is significantly greater than that of
oral contraceptives
– increase the risk of adverse events, such as
thromboembolism
Cont’d
 3. Vaginal ring
• It contains ethinyl estradiol and
etonogestrel
• It is inserted into the vagina
• Left in place for 3 weeks and then
removed
• No ring is used during the fourth
week
• Withdrawal bleeding occurs
 4. Progestin-only pills
• Products containing a progestin only
• Usually norethindrone (called a “mini-pill”)
• Taken daily on a continuous schedule
• It deliver a low, continuous dosage of drug
• Less effective than combination products
• They may produce irregular menstrual cycles
• Used in
– Breast-feeding
– Patients intolerant to estrogen
– Smokers (increased risk of cardiovascular complication in
combination Ocs)
 5. Injectable progestin
• Example: Medroxyprogesterone acetate
• Administered via IM or SC every 3 months
• It provides high sustained levels of progestin
– Many women experience amenorrhea
• Return to fertility may be delayed for several months after
discontinuation
• Adverse effects
– Weight gain
– Bone loss (predispose patients to osteoporosis and/or
fractures)
• Should not be continued for more than 2 years
Cont’d
 6. Progestin implants
• Example: Etonogestrel
• Subdermal implant
• Offers contraception for approximately 3
years
• The effect is totally reversible when surgically
removed
• Less effective in obese
• Side effects
– Irregular menstrual bleeding
– Headaches
 7. Progestin intrauterine device

• A levonorgestrel-releasing intrauterine system

• Offers contraception for 3 to 5 years
• Good for those desire long-term contraception
• OR who have contraindications to estrogen
therapy
 8. Postcoital contraception
• Emergency contraception
• Should be taken as soon as possible
• After unprotected intercourse and preferably
within 72 hours
• Reduces the probability of pregnancy
• It uses high doses of levonorgestrel
(preferred)
• Or high doses of ethinyl estradiol plus
levonorgestrel
– The progestin-only emergency
contraceptive regimens are better
tolerated than the estrogen–progestin
combination regimens
Cont’d
 Mechanism of action
• Estrogen
– Provides a negative feedback on the release of LH
and FSH by the pituitary gland
• Thus preventing ovulation
• Progestin
– Thickens the cervical mucus
• Thus hampering the transport of sperm
• Withdrawal of the progestin
– Stimulates menstrual bleeding during the placebo
week
 Adverse effects
• The most common adverse effects with estrogens are
– Breast fullness
– Fluid retention
– Headache
– Nausea
– Increased blood pressure
• Progestins may be associated with
– Depression
– Changes in libido
– Hirsutism
– Acne
• Adverse effects are most common among women who are over age 35
and smoke