REPRODUCTIVE PHARMACOLOGY

Dr. A.A. MURTALA

 HIGHLIGHTS

• Menstrual cycle and ovulation

• Drugs affecting fertility

• Drugs affecting uterine muscle contractility

 HYPOTHALAMUS

• Gonadotrophin-releasing hormone GnRH

• Follicle-stimulating hormone (FSH)

• Luteinising hormone (LH) or interstitial cell-

stimulating hormone
 FSH

• Stimulates the growth of the ovum and the

Graafian follicle in the female and gametogenesis
in the male;
• With LH, stimulates the secretion of oestrogen
throughout the menstrual cycle and progesterone
in the second half
 LH

• Stimulates ovulation and the development of the

corpus luteum;

• With FSH, stimulates secretion of oestrogen and

progesterone in menstrual cycle;

• In male, regulates testosterons secretion

 OVULATION

•OVULATION is the release of a mature egg

from the ovary.

•Occurs in response to high concentrations

of FSH and LH.
1. HYPOTHALAMUS RELEASES GONADOTROPIN-RELEASING HORMONE (GnRH).
This stimulates the anterior pituitary to release FSH and LH.
2. FSH STIMULATES MATURATION OF PRIMARY OOCYTE IN AN IMMATURE
FOLLICLE.
3. FOLLICLE PRODUCES ESTROGEN. Estrogen: (A) builds the uterine wall (the
endometrium).
4. HIGH LEVELS OF ESTROGEN FURTHER STIMULATE SECRETION OF LH BY
ANTERIOR PITUITARY. This plus FSH also causes ovulation of the secondary
oocyte – leaving follicle without egg (the corpus luteum).
5. CORPUS LUTEUM SECRETES ESTROGEN AND PROGESTERONE. This maintains
the endometrium for 15-16 days and inhibits LH.
6. (If oocyte is not fertilized and implanted in the uterine wall) CORPUS
DEGENERATES (TO CORPUS ALBICANS) AND STOPS PRODUCING ESTROGEN
AND PROGESTERONE.
7. WITHOUT ESTROGEN AND PROGESTERONE, ENDOMETRIUM BREAKS DOWN –
MENSTRUATION OCCURS. Menstruation is the sloughing off of the enlarged
endometrial wall along with blood and mucous.
 HORMONAL REGULATION IN NONPREGNANT FEMALE
(UTERINE CYCLE)

1. HYPOTHALAMUS RELEASES GONADOTROPIN-RELEASING

HORMONE (GnRH). This stimulates the anterior pituitary to
release FSH and LH.
 HORMONAL REGULATION IN NONPREGNANT FEMALE
(UTERINE CYCLE)

2. FSH STIMULATES MATURATION OF PRIMARY OOCYTE IN AN

IMMATURE FOLLICLE.
 HORMONAL REGULATION IN NONPREGNANT FEMALE
(UTERINE CYCLE)

3. FOLLICLE PRODUCES ESTROGEN. Estrogen: (A) builds the uterine

wall (the endometrium); (B) inhibits secretion of FSH.
 HORMONAL REGULATION IN NONPREGNANT FEMALE
4. HIGH LEVELS OF ESTROGEN FURTHER STIMULATE SECRETION OF
LH BY ANTERIOR PITUITARY. This plus FSH also causes ovulation of
the secondary oocyte – leaving follicle without egg (the corpus
luteum). (Approximately day 15.)
 HORMONAL REGULATION IN NONPREGNANT FEMALE
(UTERINE CYCLE)

5. CORPUS LUTEUM SECRETES ESTROGEN AND PROGESTERONE.

This maintains the endometrium for 15-16 days and inhibits LH.
 HORMONAL REGULATION IN NONPREGNANT FEMALE
(UTERINE CYCLE)
6. (If oocyte is not fertilized and implanted in the uterine wall)
CORPUS DEGENERATES (TO CORPUS ALBICANS) AND STOPS
PRODUCING ESTROGEN AND PROGESTERONE.
 HORMONAL REGULATION IN NONPREGNANT FEMALE
(UTERINE CYCLE)
7. WITHOUT ESTROGEN AND PROGESTERONE, ENDOMETRIUM
BREAKS DOWN – MENSTRUATION OCCURS. Menstruation is the
sloughing off of the enlarged endometrial wall along with blood
and mucous.
 HORMONAL REGULATION IN NONPREGNANT FEMALE
(UTERINE CYCLE)

8. DECREASE IN PROGESTERONE AND LH. Low LH causes secretion

of FSH by pituitary again. The cycle repeats.
 HORMONAL REGULATION IN NONPREGNANT
FEMALE
(UTERINE CYCLE)

IF – SOMEWHERE BETWEEN:

5. CORPUS LUTEUM SECRETES ESTROGEN AND

PROGESTERONE. This maintains the endometrium for
15-16 days and inhibits LH.

And

6. (If oocyte is not fertilized and implanted in the uterine

wall) CORPUS DEGENERATES (TO CORPUS ALBICANS)
AND STOPS PRODUCING ESTROGEN AND
PROGESTERONE.

SPERM GETS TO EGG...

FERTILIZATION CAN TAKE PLACE, AND ULTIMATELY,
 HORMONAL REGULATION IN
PREGNANT FEMALES
• Recall that developiong embryo has extra-embryonic membranes:
chorion, amnion, yolk sac, and allantois.
• Chorion and allantois are embryonic contribution to placenta.
• Chorionic portion secretes HUMAN CHORIONIC GONADOTROPIN (hCG).
• hCG prevents corpus luteum from degenerrating – thus it continues to
secrete PROGESTERONE AND ESTROGEN.
• This maintains inegrity of uterine wall and inhibits subsequent ovulation
(due to lack of FSH or LH).
• Birth-control pills mimic the high estrogen/progesterone levels to trick the
body into thinking it is pregnant and thus inhibiting ovulation.
FEMALE HORMONES DURING PREGNANCY

Note high levels

of estrogen and
progesterone.
ESTROGENS AND PROGESTERONES

• Steroidal Estrogens
• Nonsteroidal Estrogens
• Progesterones
• Synthetic Progesterones
ESTROGENS AND PROGESTERONES

• Steroidal estrogens
• Natural
• estradiol
• conjugated estrogens
• Sulfate esters of estrone and equilin
• Synthetic derivatives of estradiol
• Ethinyl estradiol
• mestranol
ESTROGENS AND PROGESTERONES

• Steroidal estrogen
• Oral with little first pass metabolism
• Micronized estradiol, ethinyl estradiol, mestranol, and
conjugated estrogens
• Ethinyl estradiol and mestranol –longer half-life
• Transdermal estradiol – release drug over 3 days to one
week
• Injectable –long acting
• Estradiol cypionate and valerate
ESTROGENS AND PROGESTERONES

• Steroidal estrogen
• Indications
• Treat primary hypogonadism (Breast development, pubic hair,
also affect menstrual cycle).
• Hormone replacement therapy
• Combination with progesterone
• oral contraception
• Acne vulgaris
• Dysmenorrhea (cramps and pains during period)
• Inoperable prostate and breast cancer
ESTROGENS AND PROGESTERONES

• Steroidal estrogen
• Adverse effects
• Breast tenderness
• Headache
• Edema
• Nausea
• Vomiting
• Anorexia
• Change in libido
ESTROGENS AND PROGESTERONES

• Steroidal estrogen
• Adverse effects
• Hypertension
• Thrombo-embolic disorders
• Gallbladder disease
• Caution
• Hepatic diseases
• Endometriosis (Can trigger inflammation & pains)
• Thrombo-embolic diseases (It increases the risk of venous
thrombosis).
ESTROGENS AND PROGESTERONES

• Nonsteroidal estrogens
• DES diethylstilbestrol
• Well-absorbed po

• No first-pass metabolism

• Treat inoperable prostate and breast cancer

ESTROGENS AND PROGESTERONES

• Progesterone
• Megesterol, hydoxyprogesterone caproate,
medroxyprogesterone acetate
• Suppress ovarian function
• Treat dysmenorrhea, endometriosis, uterine bleeding
• Prevent uterine hyperplasia and endometrial cancer
ESTROGENS AND PROGESTERONES

• Synthetic progestins
• Desogestrel, levonorgestrel, norethindrone,
norethynodrel, norgestimate
• Varying degrees of estrogenic, antiestrogenic, and
androgenic activity
ESTROGENS AND PROGESTERONES

• Hormone Replacement Therapy

• Relieve vasomotor symptoms and atrophic vaginitis
• Decrease LDL and increase HDL
• Reduces osteoporosis
ESTROGENS AND PROGESTERONES

• Hormone Replacement Therapy

• Oral
• Conjugated equine estrogens – Premarin
• Synthetic conjugated estrogens – Cenestin
• Esterified estrogens – Menest
• Micronized 17B-estradiol – Estrace
• Estropipate –Ortho-Est, Ogen
• Ethinyl Estradiol - Estinyl
ESTROGENS AND PROGESTERONES

• Hormone Replacement Therapy

• Transdermal
• 17B-estradiol matrix patch –Alora, Climara, Esclim, Vivelle
and Vivelle-Dot
• 17B estradiol reservoir patch - Estraderm
ESTROGENS AND PROGESTERONES

• Hormone Replacement Therapy

• Vaginal
• Creams
• 17B-estradiol – Estrace
• Conjugated equine estrogens – Premarin
• Tablet
• Estradiol hemihydrate - Vagifem
ESTROGENS AND PROGESTERONES

• Hormone Replacement Therapy

• Progestogen only
• Medroxyprogesterone acetate – Provera
• Norethindrone – Aygestin
• Progesterone USP (peanut oil) - prometrium
ESTROGENS AND PROGESTERONES

• Contraceptives
• Estrogen-progestin combination
• Decrease LH and FSH and prevent mid-cycle LH surge that
stimulates ovulation
• Adverse effects
• Avoid in smokers older than 35 years
• Interactions – barbs, carbamazepine, phenytoin, antibiotics
decrease effectiveness, increase synthesis of vit K clotting
factors-warfarin
 ANTIESTROGENS

• Are competitive antagonists or partial agonists.

• Tamoxifen is used in oestrogen-dependent
breast cancer (block 17β-estradiol, E2 at receptor
site)and male infertility.
• Clomiphene induces ovulation by inhibiting the
negative feedback effects on the hypothalamus
and anterior pituitary.
 ANTIESTROGENS

• Selective drugs that are oestrogen agonists in

some tissues but antagonists in others are being
developed.

• Raloxifene (one such drug) is used to treat and

prevent osteoporosis
 CLINICAL USE ANTIESTROGENS

• To treat oestrogen-sensitive breast cancer

(tamoxifen).

• To induce ovulation (clomiphene) in treating

infertility
 ANTIANDROGENS

• Antiandrogens (e.g. flutamide, cyproterone) are

used as part of the treatment of prostatic cancer.
• Drugs can have antiandrogen action by inhibiting
synthetic enzymes.

• E.g.Finasteride inhibits the enzyme (5α-

reductase) that converts
 ANTIANDROGENS

• testosterone to dihydrotestosterone which has

greater affinity for androgen receptors in the
prostate gland.

• It is used to treat benign prostatic hyperplasia

(BPH)
 ANTIANDROGENS

Terazosin or tamsulosin are α1-adrenoceptor

antagonists,

• Terazosin or tamsulosin are more effective (for

BPH) by relaxing smooth muscle in the capsule of
the prostate gland
 GONADOTROPHIN-RELEASING
HORMONE AND GONADOTROPHINS
• The gonadotrophins, follicle-stimulating hormone
and luteinising hormone, are glycoproteins.
• Preparations of gonadotrophins (e.g. chorionic
gonadotrophin) are used to treat infertility caused
by lack of ovulation.
• Danazol is a modified progestogen that inhibits
gonadotrophin production by an action on the
hypothalamus and anterior pituitary
 GONADOTROPHIN-RELEASING
HORMONE AND GONADOTROPHINS

• Gonadotrophin-releasing hormone is a
decapeptide; gonadorelin is the synthetic
form.
• Nafarelin is a potent analogue.
• Given in pulsatile fashion, they stimulate
gonadotrophin release; given continuously,
they inhibit it.
 GONADOTROPHIN-RELEASING
HORMONE AND GONADOTROPHINS
• Synthetic GnRH is termed gonadorelin.
Numerous analogues of GnRH, both agonists and
antagonists, have been synthesised.
• Buserelin, leuprorelin, goserelin and
nafarelin are agonists, the last being 200 times
more potent than endogenous GnRH