Female hormones and contraception

FEMALE HORMONES AND CONTRACEPTION

RESIDENT: FARIHA FATIMA

JR-2

Scheme Of Presentation:

Introduction Estrogens Selective Estrogen Receptor Modulator Progestins Anti-Progestins Selective Progesterone Receptor Modulator Contraception

Introduction

Estrogens and progestins are steroid hormones with numerous physiological

actions.

In women, these include developmental effects, control of ovulation, cyclical

preparation of the reproductive tract for fertilization and implantation, and

metabolic actions.

Estrogens also have important actions in males, including effects on bone,

spermatogenesis, and behavior.

Neuroendocrine control of the menstrual cycle

Untoward Responses:

CONCERN ABOUT CARCINOGENIC ACTIONS:

Early studies established that estrogens can induce tumors of the breast, uterus, testis, bone,

kidney, and other tissues in various animal species.

Estrogen use during pregnancy also can increase the incidence of nonmalignant genital

abnormalities in both male and female offspring; pregnant women should not be given

estrogens.

In men: gynaecomastia, feminization, decreased libido

Currently approved SERMs in the U.S. are tamoxifen

(NOLVADEX,), raloxifene (EVISTA), and toremifene (FARESTON).

ANTIESTROGENS: CLOMIPHENE AND FULVESTRANT

These compounds are pure antagonists in all tissues.

Clomiphene (CLOMID, SEROPHENE, others) is approved for the

treatment of infertility in anovulatory women;

Fulvestrant (FASLODEX, ICI 182,780) is used to treat breast cancer

in women with disease progression after tamoxifen.

Fulvestrant:

It is a pure anti-estrogen( a selective estrogen receptor

downregulator)

It downregulates ER by promoting degradation of receptors by

proteosomal enzymes.

Used to treat tamoxifen resistant breast cancer.

Therapeutic Uses: Breast Cancer Osteoporosis Infertility

Progestins:

Mechanism of Action:

Physiological and Pharmacological Actions

NEUROENDOCRINE ACTIONS : Progesterone produced in the luteal phase of the

cycle decreases the frequency of GnRH pulses, which is one mechanism of action of

progestin-containing contraceptives.

REPRODUCTIVE TRACT: Progesterone decreases estrogen-driven endometrial

proliferation and induces a secretory endometrium; the abrupt decline in progesterone at

the end of the cycle is the main determinant of the onset of menstruation.

Progesterone also influences the endocervical glands, changing the abundant watery

secretion of the estrogen-stimulated structures to a scant, viscid material.

Finally, progesterone is essential to maintain pregnancy, at least partly by suppressing

uterine contractility.

MAMMARY GLAND :

Mammary gland development requires both estrogen and progesterone.

During pregnancy, and to a minor degree during the luteal phase of the cycle,

progesterone acts with estrogen to induce proliferation of the acini of the mammary

gland.

CNS EFFECTS : Progesterone increases basal body temperature by about 0.6°C

at midcycle when ovulation occurs.

ANTIPROGESTINS:

The antiprogestin, RU 38486 (often referred to as RU-486) or mifepristone, is

available for the termination of pregnancy.

Antiprogestins have several other potential applications, including uses as contraceptives, to induce labor, and to treat uterine leiomyomas, endometriosis, meningiomas, and breast cancer.

THERAPEUTIC USES: Mifepristone (MIFEPREX) is used to terminate early pregnancy.

A prostaglandin (e.g., intramuscular sulprostone, intravaginal gemeprost, or

oral misoprostol) is given 48 hours after the mifepristone(600mg oral) to

ensure expulsion of the detached blastocyst.

The success rate with such regimens is >90% among women with

pregnancies of <7 weeks’ duration.

S/E: failed abortion, prolonged bleeding, vomiting,etc.

Selective Progesterone Receptor Modulator:

Their actions differ in different organs/tissues (agonist activity

where coactivators predominate and antagonist where corepressors

are in excess). Examples include:

Ulipristal – for emergency contraception

Proellex – under clinical trials to treat endometriosis, leiomyoma,

breast CA.

Asoprisnil – under investigation for treatment of leiomyoma.

CONTRACEPTIONInterception in the birth process at any stage ranging from ovulation to ovum implantation.

A) ORAL CONTRACEPTIVES:

1) COMBINATION PILLS

Monophasic

Biphasic

Triphasic

2) MINI PILLS (PROGESTIN ONLY PILLS)

3) POST COITAL (MORNING AFTER) PILLS

4) CENTCHROMAN

B) INJECTABLE CONTRACEPTIVES:

5) ESTRADIOL VALARATE+17-HYDROXYPROGESTERONE CAPROATE

6) ESTRADIOL CYPIONATE+MEDROXYPROGESTERONE ACETATE

7) DEPOT MEDROXYPROGESTERONE ACETATE

C) RECENT CONTRACEPTIVE METHODS:

1) LEVONORGESTREL subcutaneous implant

2)LEVONORGESTREL intrauterine inserts

D) HORMONAL CONTRACEPTION IN MALES:

1) TESTOSTERONE UNDECANOATE

2) TESTOSTERONE UNDECANOATE + DMPA

3) GOSSYPOL

COMBINATION PILLS:

- Most popular- Formulation with low doses of estrogens and progestins

BIPHASIC / TRIPHASIC PILLS:

Biphasic : have a fixed dose estrogen for 21 days but increasing doses of

progesterone during 2 successive phases i.e, from 1-10 and 11-21 days.

Eg, ethinyl estradiol (35microgm) + norethidrone (0.5mg)

Triphasic : provide a bit higher dose of E near midcycle but increasing doses of P

for 3 consecutive phases. For eg.

EE 30 microgm + norgestrel 0.05mg (day 1-6)

EE 40 microgm + norgestrel 0.075mg (day 7-11)

EE 30 microgm + norgestrel 0.125mg (day 12-21)

ADVERSE EFFECTS:

ESTROGENIC PROGESTOGENIC

Nausea increased appetiteMigraine weight gainBreast tenderness acneMild edema hirsutismVertigo decreased libidoLeg cramps increased body tempUterine cramps breakthrough bleedingPrecipitation of diabetes monilial vaginitis amenorrheaContraindications: genital CA, diabetes, breast CA, hypertension, undiagnosed vaginal bleeding,etc.

Minipill (progestin only pill)

A low-dose progestin only pill is taken daily continuously without

any gap. The menstrual cycle tends to become irregular and

ovulation occurs in 20-30% women,

The efficacy is lower (96-98%) compared to 98-99.9% with

combined pill.

Eg. Norethindrone 350 microgm or Norgestrel 75.

S/E: acne , hirsutism and amenorrhea.

Postcoital(emergency) contraception

Levonorgestrel 0.5 mg + ethinylestradriol 0.1mg (2 ovral tablets) taken

as early as possible but within 24hours of unprotected intercourse and

repeated after 12 hours. Till recently this regimen called the Yuzpe

method has been the most popular.

Levonorgestrel alone 0.75 mg taken twice with 12 hour gap within

72hours of intercourse.

Mifepristone 600 mg single dose taken within 72hours of intercourse

has been used in China, Europe and few other countries with high

success rates and fewer side effects than Yuzpe method.

Injectables:

Long acting progestin alone injected once month for 2-3 months Two compounds are being marketed:

(a)Depot medroxyprogesterone acetate (DMPA) 150 mg at 3-month intervals.

starting just after parturition or during the first 5 days of the cycle.

Side effects: irregular bleeding ending up in amenorrhea and anovulation.

Mechanism of action: same as that of minipills.

(b)combined estrogen progestin injectable: estradiol cypionate 5mg + DMPA 25mg im once in 2 months.

Side effects:

Mechanism of action: same as that of combination pills

Recent contraceptive methods:

Norplants : it contains a set of 6 capsules filled with 36mg of levonorgestrel for sc implantation on the inside of the upper arm.

It is effective upto 5 yrs if kept implanted.

Intrauterine inserts: a device which releases levonorgestrel at a rate of 20microgm/day into the uterine cavity for a period of 5 yrs.

Hormonal contraception for men:

Recent WHO sponsored trials revealed that initial dose of 1000mg im of

testosterone undecanoate followed by 500 mg maintenance dose revealed

reversible azoospermia in majority of men.

In another study DMPA + testosterone undecanoate : 97% male volunteers

revealed reversible azoospermia within 3 months of initiating the study with

minimum side effects.

Gossypol : orally effective non-steroidal drug obtained from cotton seed and used in

China.

Dose: 20mg/day for initial 2-3 months followed by 50-60mg/day as maintenance dose for not more than 2yrs at a stretch decreases sperm motility drastically within 3 months.

Side effects: hypokalemia,

muscle weakness,

transient paralysis.