Drugs influencing Fertility and Reproduction

Question 1

Mention the three categories of steroids secreted by the gonads

Answer 1

1. Estrogens: Estradiol, Estrone and Estriol
2. Progestins: Progesterone
3. Androgens: Testesterone

Question 2

Synthesis of Progesterone

Answer 2

Pregnenlone is the precursor to progesterone as well as to dehydroepiandrosterone and androstenedione(2 androgens secreted by the adrenal gland) and to testosterone

Question 3

What converts adrenal and gonodal androgens to Estrogen

Answer 3

Aromatase-enzyme that forms the aromatic A-ring necessary for the selective high-afinity binding of estradiol, estrone and estrol to ERs

Question 4

Production of Testosterone

Answer 4

Testosterone is produced in the female ovarian thecal cells and secrete small quantities of testosterone.

In males 94% of it is from the Leydig cells and 5% of it is from the adrenal cortex.

Question 5

Synthesis of Testosterone

Answer 5

It is synthesised in the same pathways as in the ovaries.

It is subsequently converted to Dihydrotestosterone(DHT) by 5-Alpha-reductase in the prostate, hair follicles and skin.

In plasma, testosterone is primary bound to a steroid-binding globulin.

In the liver,It is converted to androstenedione and other metabolites including sulfate and glucuronide metabolites which are excreted in urine and some is feces.

Question 6

What can DHT formation inhibition cause

Answer 6

If DHT formation is inh., this significantly reduces the androgenic stimulation of the prostate gland and hair follicles

Question 7

Function of Estrogens

Answer 7

Promote the dev. of the fallopian tubes, uterus and vagina as well as secondary sex characteristics such as breast development, skeletal growth and axialary and pubic hair patterns

Sensitize moyometrium to oxytocin at parturiton facilitaiting labour

Stimulate protein synthesis in brain and may affect mood and emotions

Influcence the distribution of fat around the body

Enhance blood coagulation by increasing the synthesis of clotting factors

Prevent osteoperosis b yinhibiting bone reabsorptions

Responsible for the epiphyseal closing in both males amd females,which haults linear growth

Decreases the levels of LDL cholesterol and lipoprotein(a) while increasing the levels of HDL cholesterol

Question 8

Which hormone is secreted should pregnancy occur

Answer 8

Human chorionic Gonadotropin-which maintans the pproduction of progesterone by the corpus lutuem.

The placenta then becomes the predominant progesterone source

Thios hormone serves to maintain pregnancy and prevents endometrial sloughinh and miscarraige

Question 9

Funtions of Progesterone

Answer 9

Increases basal body temperature by 0.5 to 0.8 at ovulation and throughout the luteal phase

Affect emotional state

Have mild mineralocorticoid(salt-retaining) properties

Question 10

Testosterone

Answer 10

LH stimulates testosterone synthesis in Leydig cells whereas FSH promotes spermatogenesis by Sertoli cells in the seminiferous tubules

Sertoli cells also produce a protien called inhibin which acts in concert with DHT as a feedback regulator of FSH secretion by pituitary

Question 11

Functions of Testosterone

Answer 11

It is responsible for the development of the primary and secondary sex characteristicsin maled during puberty

Promotes sexual function by stimulating the growth of the penis, scrotum, seminal vesicles and prostate gland.

Growth of the larynx, thickening of the vocal cords,and growth of the facial, axillary and pubic hair

Increase the body lean mass and accelerate epiphyseal closure

Development of acne in both sexes by increasing sabaceous gland activity and sebum production

Androgens also increase the production of EPO in the kidneys and decrese levels of HDL cholesterole

Question 12

Estogens:
MOA
Types and names
Preperation

Answer 12

MOA: Estradiol and other estrogens bind to ERs found on the inside and on the surface of target cells of the reproductive system and elsewhere

Types: Natural and Synthetic

Preparation: Oral, Parenteral, Topical and Transdermally

Question 13

Natural Estrogens are:

Answer 13

17β-Estradiol
Estrone
Estriol and
Equilin

Are produced by the ovaries (Used in contraception)
Equilin(horse)
Natural ES:

• 17β-Estradiol is the major natural ES in humans, half-life of 0.5 - 2 hr.
• Other human natural ES are, Estrone and estriol
• The horse’s natural estrogens is quilin
• Natural ES have a short half-life and unstable, as such, there are used only after modification to synthetic estrogens with better pharmacokinetic advantages

Question 14

Synthetic Estrogens (classification):

Answer 14

i) Estradiol derivatives:

ii) Conjugated estrogens:

Question 15

Estradiol derivatives:

Answer 15

Most of the synthetic ES are derivatives of 17β-estradiol:

a) Modified estradiol: Ethinylestradiol and mestranol

• Ethinylestradiol = ethynnylated estradiol (active)
• Mestranol = methyl-ether-ethinylesradiol. In the body, it is converted back to ethinylestradiol (active form).
• Advantage: reduced first pass metabolism, and longer half-life > 20 hrs

b) Estradiol esters (conjugates): Estradiol cyproate & estradiol valerate):

• Long acting (extended release) forms of estradiol.

• Estradiol valerate = Estradiol plus the fatty acid valeric acid.
• Estradiol cyproate = Estradiol plus the fatty acid cypionic acid

Question 16

Conjugated Estrogens

Answer 16

ii) Conjugated ES:

The natural ES molecule is conjugated to a sulphate group via an ester bond => Estrone-SO4, equilin-SO4

In the body, the ester is hydrolysed to release the ES (estrone/equilin)

Advantage: The sulphates exhibit less first pass metabolism

Products: Usually, the two estrogens sulphates are combined in different proportions to achieve optimum activity.

Primarin is a conjugated ES = 70% estrone-SO4 + 30% quilin SO4

Question 17

Estrogen, MOA and General

Answer 17

Uses:
• Hormonal replacement therapy (HRT) and Contraception

Mechanism of action:
• Bind to intracellular ES receptors&raquo_space; influence expression

Resultant effects:
• As HRT: maintains physiology function of estrogens (low doses used to achieve normal estrogen levels, premarin)

• As contraceptive: it inhibits ovulation by feed back inhibition of production of pituitary hormones (higher doses are used; estradiol derivatives).

Pharmacokinetic issues:
• Estrogens are metabolized by the liver
• Undergo extensive enterohepatic metabolism & re-cycling
• Excreted in the urine as conjugates

Question 18

Indications of Estrogen

Answer 18

Treatment of menopausal symptoms, e.g., hot flushes and vaginal dryness.

Treatment of Acne vulgaris & dysmenorrhea

Treatment of primary hypogonadism

After surgical removal of ovaries

Maintenance of the UTI and ↓ bladder problems

In HRT, low doses are used, aim is to achieve normal
estrogen levels and function

Question 19

1

Answer 19

2

Question 20

3

Answer 20

4

Question 21

5

Answer 21

6

Question 22

Adverse Effects of Estorgen

Answer 22

Common: Breast tenderness, headache, edema, nausea, vommitng and annorexia

Serious: Hypertension, Thromboembolic disorders and Gallbladder disease

Question 23

Mechanism by which Estrogen causes serious Adverse Effects

Answer 23

Hypertension: Attributed to the increased angiotensinogen synthesis and formation of Angiotensin II

Thromboembolic Disorders: Increased hepatic synthesis of clotting factos

Gallbladder disease: Estogens increase cholesterol excretion in bile, accounting to the tendency to cause gallstones.

In additon E increase the risk of breast cancer

Question 24

Relative and Absolute contraindications for the use of Estrogen

Answer 24

Estrogen’s are CI in pregnancy and should be avoided in ladies who have uterine fibroids.

Estrogen can be used with great caution in women with hepatic disease, endometriosis, thromboembolic disease or Hypercalcemia

Question 25

Why are the natural progestins unsuitable for use as drug theraphy

Answer 25

They undergo extensive first-pass metabolism after oral administration and has a short plasma half-life.
To extend the oral bioavailability and half-life, esters of progesterone have been developed

Question 26

Name the progesterone esters

Answer 26

Megestrol(0)

Hydroxyprogesterone caproate(long acting intramuscular preparation)

Medroxyprogesterone acetate(MPA)-(O or I/M)

Question 27

Metabolism of progesterone in detail

Answer 27

Folllowing absorption, the progesterone estrs are bound to albumin in the circulation. The esters are converted to several hydroxylated metabolites and pregnanediol glucuronide in the liver, and the metabolites are excreted in the urine

Question 28

Clinal hazards of using progesterone alone for dysfunctional bleeding

Answer 28

Progesterone esters are used to suppress ovarian function in the treatment of dysmenorrhea, endometriosis and uterine bleeding.

Progesterone derivatives/esters-Produce the feedback inhibition of gonadotropin secretion by the pituitary gland.

In HRT, the progesterone esters are used in combination with estrogens to decrease the incidence of estrogen-induced irregular bleeding and prevent uterine hyperplasia and endometrial cancer.

Question 29

Synthetic progestins

Answer 29

Are primarily used as oral contraceptives, but they are also used to treat dysmenorrhea, endometriosis and uterine bleeding in the same manner as progesterone esters.

Question 30

Structure of synthetic progesterones

Answer 30

Most of them are derivatives of 19-nortesterone esters(Testosterone without a methyl group on carbon-19) and stimulate varying degrees of estrogenic, antiestrogenic and androgenic activity

They contain molecular entities that increase their oral bioavailabilty and duration of action.

Their half-lives ranges from 7-24 hours, whereas the half-life of progesterone is only about 5 minutes.

Question 31

Examples of Synthetic progestins

Answer 31

Norgestrel

Desogestrel

Norgestimate

Drospirenone

Question 32

Drospirenone

Answer 32

Spironolactone derivative with significant antiandrogenic effects

Question 33

Discuss Hormonal Contraceptives

Answer 33

They are devices or drugs, devices which release drugs that prevent conception, the fertilization of an egg by the sperm and resulting pregnancy.

Contraceptives act locally in the female reproductive tract.

These include agents that kill sperm on the way to the egg,called Spermicides-most of them contain nonoxynol-9,detergent that disrupts the cell membrane of the sperm-Increase the contraceptive efficiacy of condoms and other barrier methods

Barrier methods include condoms for both males and females(Diaphragm and cervical caps) which prevent prevent sperms from reaching the uterus and fertilizing the ovum.

Intra-uterine Devices-IUD’s are available that prevent implantation of the blastocyst, some relase progestin drugs.

Other contraceptives are administered orally or by injection: Oral-birth control pills, contain female sex hormones that prevent ovulation,most contain both and es and progestin while a few contain only a progestin

Progestin-only contraceptives are also available for administration as intramuscular injections, subdermal implants or relased from IUD’s.

The last group of agents is called Long-Acting Reversible Contraceptives(LARCs)

Drugs that are available to prevent pregnancy after unprotected sex are know as emergency contraceptives

Question 34

Mechanism of Action

Answer 34

The estogen-progestin act by feedback inhibition of GnRH secreted fromthe hypothalamus leading to decreases gonadotropin secretion and inhibitoon of ovulation

Es: Reduce FSH secretion

Progestin: Inhibits the midcycle LH surge required for ovulation

Question 35

Explain the terms Monophasic, Biphasic and Triphasic

Answer 35

Normally all COC contain the a fixed ES dose, and only the Progestins dose is changed, leading to monophasic and biphasic products1. Monophasic_21 tabs ES & fixed PG dose & 7 placebos = 28 days• Aim to maintain cycle control and ovulation suppression2. Biphasic and triphasic tabs_They try to mimic normal cycle by increasing PG dose later in cycle, increased after 7 (biphasic) and 14 days (triphasic)• Disadvantages_- cannot adjust cycle length- causes more water retention, dysmenorrhea, PMS

Question 36

Calender Packs and Extended cycle preperations

Answer 36

Calender packs: Usually contain 21 active ingredient tablets administered on day 5 of menstrual cycle. other include 7 inert pills taken for the remainder of the cycle as a method of reinforcing daily pill administration

Extended cycle/Menstrual suppresion: Continous daily administration for 84 days followed by 7 days of inactive tablets.

These preparations contain ethinyl estradiol and levonorgestel and allow for withdrawal bleeding only 4 times a year, whereas oral es-progestin contraceptives result in 13 withdrawal bleeding episodes a year