Progestins

Recall the 6 facts of progestin

1. Progestins are group names and not single molecules

2. can be used alone for BC & hormone replacement therapy or in conjunction with estrogen in combination oral contraceptive

3. Used to treat endometriosis & pain associated with it

4. Used to treat breast, uterus, and kidney cancer by changing the cell’s ability to use other hormones

5. secreted during the second half (luteal phase) in preparation for pregnancy

6. stimulate angiogenesis in the endometrium when egg is fertilized & implanted

What are the steps in the synthesis of endogenous progestin?

2 Types of Pregestins: Natural progesterone

• important for maintaining pregnancy by suppressing menstruation & uterine contractility

• switch proliferative to secretory state in preparation of the uterus for implantation of fertilized egg in the second half of menstrual cycle (day 15-28)

what are the 4 uses of synthetic progestins & their 2 types

• contraceptions

• menopause symptoms

• endometriosis

• dysfunctional uterine bleeding

• Progesterone derivatives

• 19-NORTESTOSTERONE DERIVATIVES

What are the 2 types of 19-nortestosterone derivatives & what do they do?

• estranes

• gonanes

• decrease androgenic synthesis

What type of receptors is progestin receptor, PR-A,PR-B?

• progestin receptor: type I nuclear hormone receptors

• PR-A & PR-B: type II

What does PR-A receptor do?

inhibits PR-B mediated transcription when both are present in the same cell as well as repress estogen, androgen, glucorticoid, and mineralocorticoid receptor activities

describe the signaling steps of progestin with its receptors

1.Hormone binds to NR and HSP dissociates

2. Dimerization between two NR-Ligand

3. Translocation to nucleus

4. NR dimer binds to HRE of DNA

5. Recruitment of coactivators and proteins

for transcription to mRNA

6. New protein to modify cell function

Endogenous progesterone maintains what ?

pregnancy

What does contraceptives (progestin only-mini pill) do?

• prevents the LH surge & inhibits ovulation

• thickens cervical mucus

• thins lining of uterus making implantation less likely

Explain how synthetic progestin treats endometriosis

stimulates atrophy or regression of endometrial lesions

How does hormone replacement therapy (HRT) work?

• added to estrogen to reduce risk of uterine cancer in women who haven’t had a hysterectomy

• inhibits estrogen induced proliferation of endometrium

Side Effects of Progestin only contraceptives (6)

• irregular, unpredictable spotting and breakthrough bleeding

• Acne

• headache

• mood changes

• weight gain

• decrease bone density

Progestin only contraceptives contraindications (10)

presence or hx of:

• thromboembolic or cerebrovascular disease

• MI or CAD

• Congenital hyperlipidemia

• carcinoma of the breast or female reproductive tract

• impaired liver function

• migraine headaches

• hypertension

• DM

• Pregnancy

• gallbladder disease

What is the structural difference between natural & synthetic progestin?

• -CH3 at C6 on some synthetics

• -ene at C6-7

• Substitutions at C17 or C20

What are the 4 available forms of progesterone

• Crinone Vaginal gel

• Endometrin Vaginal Insert

• Progesterone IM injection sol

• Progesterone/PROMETRIUM oral capsule

Pharmacokinetics of PO progesterone

• low oral bioavailability

• extensively metabolized

• highly protein bound

• large Vd

• PK values are highly variable

5 SARs for Progesterone derivatives

• Pregnane nucleus (required)

• 3-keto & 4-5 double bond (required)

• 20-keto

• 17-hydroxyl ester (increases activity)

• 6-methyl (increases oral stability)

6 SARs for 19-norprogestins derivatives

• estrane nucleus

• 3-keto & 4-5 double bond

• 17-beta OH

• 17-alpha-ethynyl group

• 18-ethyl (in place of methyl)

• 11-exocyclic double bond