this ppt details about progesterone right from it's discovery to it's large scale synthesis via marker's degradation. structure activity relationship of all progesterone derivatives, it' s newer applications in postpartum depression in the form of Brexanolol etc.. also the research going on this topic. contraceptives are covered, mainly pharmacotherapy of contraception, newer emerging tools for contraception.

1. Dr.shankar Gejji 1
Progesterone and Contraceptives
Presenter: Dr. Shankar Gejji (JR-1)
Department of Pharmacology and Therapeutics
King George’s Medical College,Lucknow, U.P, India
Gmail ID: drshankargkgmu@gmail.com
01-07-2025

2. Dr.shankar Gejji 2
Content:-
• Introduction to progesterone
• Types and mechanism of action progesterone
• Pharmacokinetics and actions of progesterone
• Contraceptives and its types
• Hormonal contraceptives
• Emerging contraceptive techniques
• Summary
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3. Dr.shankar Gejji 3
Specific learning objectives :-
By the end of this teaching-learning session, co-learners will be able to -
• Enumerate types of progesterone
• Explain the MOA & pharmacological actions of progesterone
• Define contraception
• Enumerate types of contraceptives
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4. Dr.shankar Gejji 4
Introduction:-
• Progesterone
• Natural steroid hormone
• Plays key role in menstrual cycle, pregnancy and embryogenesis
• Chemical Structure:
• C21 steroid nucleus
• Primary Source: Corpus luteum, placenta (pregnancy), adrenal glands
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5. Dr.shankar Gejji 5
Historical Milestones in Progesterone
• 1929: Discovery of corpus luteum hormone
• 1934: Butenandt and Westphal isolated progesterone
• 1939: Marker degradation – breakthrough for semi-synthesis
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6. Dr.shankar Gejji 6
Types of Progestins:-
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Natural Progestin Progesterone (C21)
Synthetic
Pregnanes (C-21)
Medroxyprogesterone acetate
Estranes (C-18) Norethindrone – derived from 19-nortestosterone
Gonanes (C-18) Levonorgestrel – structurally improved estranges

7. Dr.shankar Gejji 7
Differences Between Progestins and Progesterone
Feature Progesterone Pregnanes Estranes Gonanes
Carbon skeleton C21 C21 C18 C18
Androgenic activity None Minimal Moderate Low
Potency Physiological Moderate High Very hIgh
examples
Natural
progesterone
Medroxyprogesterone
Cyproterone acetate
Megestrel acetate
Norenthindrone
Ethynodiol diacetate
Lynestrenol
Norethynodrel
Levonorgestrel
Desogetrel
Etonogetrel
Norgestimate
Dionogest
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8. Dr.shankar Gejji 8
Structural Activity Relationships (SAR)
• Removal of 19-methyl (in estranes) → Increases progestational potency
• Addition of ethinyl group at C17 → Increases oral bioavailability
• Gonanes (13-ethyl substitution) → High receptor affinity, minimal
androgenicity
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9. Dr.shankar Gejji 9
Mechanism of Action of Progesterone
Genomic Action:
• Binds to progesterone receptors (PR-A, PR-B)
• Modulates gene transcription → Delayed but sustained response
Non-Genomic Action:
• Acts via membrane-associated PRs
• Rapid signalling via cAMP, calcium pathways
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10. Dr.shankar Gejji 10
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Mechanism of Action of Progesterone:

11. Dr.shankar Gejji 11
Types of Progesterone Receptors (PRs)
• PR-A:
• Inhibitory isoform,
• regulates PR-B activity
• PR-B:
• Stimulatory isoform
• full transcriptional activity
• PR-C:
• Truncated
• less well understood
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12. Dr.shankar Gejji 12
Factors influencing progesterone actions:-
Balance between PR-A and PR-B → Determines tissue-specific response
Example:- PR-A dominance linked to endometrial atrophy; PR-B dominance
needed for pregnancy maintenance
Estrogen levels, receptor coactivators, and specific gene promoters
Isoform expression ratio determines tissue- specific progesterone responsiveness
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13. Dr.shankar Gejji 13
Progesterone Receptor Cross talk:-
 Interacts with:
• Estrogen receptors
• Glucocorticoid receptors
• Androgen receptors
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14. Dr.shankar Gejji 14
Pharmacokinetics:-
• Oral - High first pass metabolism in liver
• Micronized formulation - absorption through lymphatics, bypasses liver
• Binds to plasma proteins albumin-80%, cortisol binding globulin (15%)
• t ½ - 5-7 minutes
• Metabolised in the liver through reduction, hydroxylation
• Excreted in the urine as glucuronide and sulfate conjugates
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15. Dr.shankar Gejji 15
Actions of Progesterone:-
• In Endometrium: Inhibits proliferation, induces secretory changes
• In Cervix: Thickens mucus → Prevents sperm penetration
• In Breast: Promotes glandular development
• In CNS: Modulates mood, temperature regulation
• In Bone : Promotes osteoblasts proliferation
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16. Dr.shankar Gejji 16
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Action on genital tract and gonads:-
• Endometrium: Anti-proliferative, secretory transformation
• Cervix: Mucus thickening
• Myometrium: Reduces contractility → Maintains pregnancy
• Suppresses gonadotropin release (FSH, LH) → Inhibits ovulation
• Negative feedback on hypothalamus and pituitary
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18. Dr.shankar Gejji 18
Actions on CVS:
• Mild natriuretic effect via aldosterone antagonism
• May lower BP via vascular tone relaxation
• Progestins with androgenic activity → Unfavourable lipid profile
• PR-A and PR-B balance determines vasodilatory effect
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19. Dr.shankar Gejji 19
Actions on CNS:
• Modulates GABA-A receptors → Anxiolytic, sedative properties
• Thermoregulatory effects → Can prevent hot flushes
• Neuroprotective roles (recent evidence)
• PR isoform balance affects synaptic plasticity and neuroinflammation
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20. Dr.shankar Gejji 20
Uses of progesterone:
Gynecological Uses:
• Contraception (combined and progestin only pills)
• Hormone replacement therapy – used along with estrogen to counteract the risk
of endometrial carcinoma
• Treatment of dysfunctional uterine bleeding- MPA 10-20mg/day
Norethindrone -5-10mg/day
• Endometriosis management
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21. Dr.shankar Gejji 21
Obstetric Uses:
• Premenstrual syndrome/Premenstrual dysphoric disorder
• Prevention of preterm labor
• Luteal phase support
• Oncology:
• Palliative management in endometrial and breast cancer.
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22. Dr.shankar Gejji 22
Adverse effects :-
• Breakthrough Bleeding: Inadequate endometrial transformation
• Weight gain - Fluid retention via mineralocorticoid pathways
• Mood changes- Modulation of GABA and serotonin pathways
• Acne (via androgenic progestins) -Cross-activation of androgen receptors
• Breast engorgement, breast cancer
• Decreased HDL → promotes atherogenesis
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23. Dr.shankar Gejji 23
Drug interactions :-
• CYP450 Inducers: Rifampin, phenytoin → ↓ Progesterone efficacy
• CYP450 Inhibitors: Ketoconazole → ↑ Progesterone levels → Side effects
• Antagonistic interactions: With estrogens at endometrial level
• Additive effects: With other CNS depressants → Increased sedation
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24. Dr.shankar Gejji 24
Recent Advances :-
• Micronized Progesterone:
• Improved bioavailability
• Reduced first-pass metabolism
• Neuroprotective Progesterone:
Ongoing research in postpartum depression and neurodegeneration
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25. Dr.shankar Gejji 25
Let’s revise
• Progesterone plays critical roles in reproductive, cardiovascular, and nervous
systems
• Marker degradation was pivotal for progesterone’s clinical availability
• Synthetic progestins differ significantly in structure, potency, and side-effect profile
• Site-specific effects and receptor cross-talk explain progesterone’s diverse actions
• Ongoing innovations are refining its therapeutic potential
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26. Dr.shankar Gejji (JR-1) 26
Contraceptives-
Definition: Methods to prevent unintended
pregnancy by interfering with
fertilization/implantation
Can be reversible or permanent, hormonal or
non-hormonal
Essential for population control, women’s health
and reproductive autonomy

27. Dr.shankar Gejji 27
• Modern contraceptive revolution started in 1960 with the approval of the first
oral contraceptive pill, Enovid
• Pioneer contributors: Margaret Sanger, Gregory Pincus, John Rock
• Enovid: Norethynodrel + mestranol
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28. Dr.shankar Gejji 28
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29. Dr.shankar Gejji (JR-1) 29
Classification of Contraceptives
1. Hormonal Contraceptives
- Combined oral contraceptives (COCs)
- Progestin-only pills (POPs)
- Injectables, implants, patches, rings
2. Intrauterine devices (IUDs)
- Copper-based
- Hormonal (Levonorgestrel-releasing)
3. Barrier Methods
4. Sterilization

30. Dr.shankar Gejji 30
Hormonal contraceptives
1. Combined Estrogen + Progestin Preparations
- COCPs, patches, vaginal rings
2. Progestin-Only Preparations (POPs)
-Mini-pills, implants (etonogestrel), injectables (Depo-Provera)
3. Emergency Contraceptives
- Levonorgestrel, Ulipristal acetate, Mifepristone
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31. Dr.shankar Gejji 31
Mechanism of action
1. Suppress ovulation
- Negative feedback on hypothalamus → ↓ GnRH → ↓ FSH/LH
2. Thicken cervical mucus (Progestin effect) → acts as a barrier to sperm
3. Endometrial atrophy → Unfavourable for implantation
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32. Dr.shankar Gejji 32
Combined oral contraceptive pills
Composition:
- Estrogen (Ethinyl estradiol or estradiol valerate)
- Progestin (Levonorgestrel, norethisterone,
desogestrel, drospirenone)
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33. Dr.shankar Gejji (JR-1) 33
• Monophasic: Fixed dose of estrogen and progestin is given throught the cycle
Example : ethinyl estradiol(25mcg)+Norethindrone(0.8mg)
• Biphasic :-Two different progestin/estrogen doses are given
1st phase (Days 1–10): lower dose
2nd phase (Days 11–21): higher dose
Example:- Follicular phase- Ethinyl estradiol 35mcg + Norethindrone 0.5mg
Luteal phase - Ethinyl estradiol 35mcg + Norethindrone 1mg

34. Dr.shankar Gejji 34
Pharmacokinetics :
• Ethinyl estradiol: Rapid absorption, hepatic metabolism (CYP3A4)
• Progestins: Variable half-lives (e.g., levonorgestrel: 12–24 hrs)
Dosing Regimens:
• 21/7 cycle (Standard)
• Extended/Continuous cycles (e.g., 84/7 for endometriosis)
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35. Dr.shankar Gejji 35
Adverse effects:
Common: Nausea, breast tenderness, breakthrough bleeding
Serious (Rare but Critical):
• Thromboembolism(↑ risk with 3rd-gen progestins, smoking)
• Hypertension, hepatic adenomas
Contraindications:
• History of VTE, migraines with aura, smokers >35 years, liver diseases
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36. Dr.shankar Gejji 36
Progestin-Only Pills (POPs)
• Also called mini-pills
• Mechanism:
- Primarily thickens cervical mucus
- suppresses ovulation
- Ovulation occurs in 20-30% recipients
• Less efficacious(96-98%) compared to
combined oral contraceptives(98-99.9%)
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37. Dr.shankar Gejji 37
Advantages: Safe in lactation
Hypertension
Smokers
Disadvantages: Strict timing (3-hour window for efficacy)
Higher failure rate
Irregular menstrual bleeding
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38. Dr.shankar Gejji 38
Emergency contraceptives:
• Prevention of unwanted pregnancy after
unprotected sexual intercourse or contraceptive
failure
• Not intended for regular contraception as it involves
higher failure rate and side effects
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39. Dr.shankar Gejji 39
Hormonal Methods:
• Levonorgestrel (LNG) 0.75mg 2 doses 12 hours apart /1.5 mg single dose (Plan B,
i-pill) ,<72 hours
• Yuzpe method – Levonorgestrel 0.5 mg+ Ethinylestradiol 0.1 mg, 2 doses at 12
hours interval,<72 hours
• Ulipristal Acetate (UPA) 30 mg (Ella), <120 hours
• Midfollicular phase- suppresses LH surge
• Delays follicular rupture
• Mifepristone 600 mg ,<72 hours
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40. Dr.shankar Gejji 40
Non hormonal method :- Cu-T IUD
Indications:-
• Unprotected sexual intercourse
• Contraceptive failure (Example - condom breakage)
• Sexual assault
• Missed contraceptive pills
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41. Dr.shankar Gejji 41
Non-Hormonal Contraceptive Methods
• Contraceptive methods that do not rely on hormones
(estrogen/progestin)
• Preferred for women who cannot or do not want to use hormonal
methods
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42. Dr.shankar Gejji 42
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Types
• Barrier Methods: Condoms (male/female), diaphragms, cervical caps
• Intrauterine Devices (IUDs): Copper-T (Cu-IUD)
• Spermicides: Nonoxynol-9
• Natural methods : Calendar method
basal body temperature method
cervical mucus method
lactational amenorrhea method
withdrawl (coitus interruptus) method
• Permanent Methods: Tubal ligation, vasectomy

43. Dr.shankar Gejji 43
Copper IUD: Mechanism of Action
• Mechanism of Action:
• Copper ions released → toxic to sperm (impairs motility &
viability)
• Local inflammatory reaction → prevents fertilization
• May also inhibit implantation (secondary mechanism)
• >99% effective (one of the most reliable methods)
• Works immediately after insertion
• Long-term protection (up to 10 years, depending on type)
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44. Dr.shankar Gejji 44
Advantages:
• No systemic hormones (safe for breastfeeding, hypertension, smokers)
• Immediate return to fertility after removal
• Cost-effective long-term
Disadvantages:
• Heavier menstrual bleeding & dysmenorrhea (common side effect)
• Risk of expulsion/perforation (rare, <1%)
01-07-2025

45. Dr.shankar Gejji 45
Specific learning objectives achieved:-
At the end of this teaching-learning session, co-learners are now be able to-
• Enumerate types of progesterone
• Explain the MOA & pharmacological actions of progesterone
• Define contraception
• Enumerate types of contraceptives
01-07-2025

46. Dr.shankar Gejji 46
Further reading:
• Pharmacoeconomics of progesterone
• Receptor cross talk
• Allopregnanolone and other neuroactive steroids
• Cardiotonic steroids
• Emerging male contraceptive techniques
• WHO eligibility criteria for the use of contraceptives
01-07-2025

47. Dr.shankar Gejji 47
Summary
• Progesterone is a 21C steroid hormone essential for maintaining pregnancy
• Progesterone exerts it’s effects through action on nuclear and membrane
progesterone receptors
• Progesterone helps maintaining pregnancy by creating a favourable environment
in the uterus
• Lack of progesterone leads to miscarriage and preterm labor
• Contraceptives are agents used to prevent unintended pregnancy
• Contraception can be hormonal and non hormonal, planned or emergency
• Hormonal contraceptives include COCs, POPs and non-hormonal include barrier
methods, Cu-T IUCD etc..
• CATSPER AND EPPIN modulation include emerging male contraceptive techniques
01-07-2025

48. Dr.shankar Gejji 48
1. Goodman LS, Gilman A, Brunton LL, Hilal-Dandan R, Knollmann BC, editors. Goodman & Gilman's the
pharmacological basis of therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
2. Tripathi KD. Essentials of medical pharmacology. 9th ed. New Delhi: Jaypee Brothers Medical Publishers; 2024.
3.Liao PV, Dollin J. Half a century of the oral contraceptive pill: historical review and view to the future. Can Fam
Physician. 2012 Dec;58(12):e757-60. PMID: 23242907; PMCID: PMC3520685.
4.Hellier S. The changing landscape of emergency contraception. Nurse Pract. 2025 Feb 1;50(2):E1-E6. doi:
10.1097/01.NPR.0000000000000277. Epub 2025 Jan 23. PMID: 39844324.
5.Massai MR, Forcelledo ML, Brache V, Tejada AS, Salvatierra AM, Reyes MV, Alvarez F, Faúndes A, Croxatto HB.
Does meloxicam increase the incidence of anovulation induced by single administration of levonorgestrel in
emergency contraception? A pilot study. Hum Reprod. 2007 Feb;22(2):434-9. doi: 10.1093/humrep/del369. Epub
2006 Sep 15. PMID: 16980507.
References:
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49. Dr.shankar Gejji 49
Thank you
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50. Dr.shankar Gejji 50
Questions:
1. What are the types of progestins?
2. Factors influencing the actions of progesterone?
3. Drug interactions of progesterone
4. Advantages of progesterone only pills over Combined Oral Contraceptives
5. Methods of emergency contraceptives
01-07-2025