Transcript Sex Hormones and Drugs Estrogen Hypothalamus Hypothalamic-PituitaryGonadal Axis (HPG): Females GnRH AP FSH LH Tonic LH LH surge PGF2a + Progesterone Estrogens FEMALE REPRODUCTIVE SYSTEM  HORMONAL REGULATION OF OOGENSIS AND OVULATION OVULATION: sharp surge in.

Sex Hormones and Drugs
Estrogen
Hypothalamus
Hypothalamic-PituitaryGonadal Axis (HPG):
Females
GnRH
AP
FSH
LH
Tonic LH
LH surge
PGF2a
+
Progesterone
Estrogens
FEMALE REPRODUCTIVE SYSTEM
 HORMONAL REGULATION OF OOGENSIS AND OVULATION
OVULATION:
sharp surge in LH
with simulataneous
increase in FSH
Meiosis I resumes;
oocyte and surrounding
cumulus break away
and are extruded
oocyte passes into
oviduct
ECTOPIC
IMPLANTATIONS
Testosterone
Hypothalamus
-
GnRH
-
Hypothalamic-PituitaryGonadal Axis (HPG): Males
Anterior
Pituitary
Seminferous tubules:
(Spermatogenisis)
FSH
LH
Inhibin
+
Sertoli cells
-
Leydig cells
Male characteristics
Growth
Behavior: Libido, aggression
+
Testosterone
+
Aromatase Inhibitors
• Used to inhibit estrogen-dependent tumors,
metastatic breast cancer.
• But, serious estrogen-lacking side-effects:
increased risk of osteoporosis.
• Anastrozole, letrozole, exemestane,
formestane.
Receptor Antagonists
• Selective Estrogen Receptor Modulators
(SERMs).
• Are mixed agonists/antagonists.
• ERα and ERβ types are tissue-specific.
• See next slide for how SERMs are tissuespecific.
SERMs
• Tamoxifen – an ER antagonist in breast, but a
partial agonist in endometrium and bone.
• Raloxifene – ER agonist in bone, but an
antagonist in both breast and endometrium.
• Clomifene – used to induce ovulation. Is an ER
antagonist in hypothalamus and ant pit, but a
partial agonist in ovaries.
Androgen Receptor Antagonists
Flutamide and spironolactone – used to treat
metastatic prostate cancer and BPH.
Progesterone Receptor Antagonists
Mifepristone (aka RU-486) – used to induce 1sttrimester abortion.
Often admin with misoprostol (PG analogue) –
stimulates uterine contractions.
Asoprisnil – does not cause abortion, but inhibits
the growth of tissue derived from the
endometrium and myometrium.
May be used to treat endometriosis and uterine
fibroids.
Adrenal Sex Hormones
• Androgens – male hormones secreted by the adrenal
cortex in both sexes and are responsible for the
physiological effects exerted by adrenal sex hormones.
• The incr protein synthesis (anabolism), which incr
muscle and bone mass and strength, affect
development of male 2° characteristics. They incr hair
growth and libido in women. Excessive secretion:
masculine effects in women.
• Female sex hormones exert few effects. Excessive
secretion: feminine characteristics in men.
Drugs Affecting the Reproductive
System
Female hormones:
Estrogen and Progesterone
Example: Oral contraceptives (OCPs)
Estrogen prevents ovulation.
Progesterone prevents implantation of ovum,
decreases amount and increases viscosity of
cervical mucous to impair sperm motility, and
impedes motility of the ova by affecting
peristalsis of the ovaduct.
Infertility
Clomifene and Tamoxifen – anti-estrogens – work by
inhibiting the negative feedback of estrogens in the
hypothalamus  Incr release of LH and FSH.
Gonadotropins – used in women who lack approp pit
function or do not respond to clomifene therapy.
Treatment starts with daily inj of menotrophin (LH =
FSH amts) or urofollitropin (FSH), followed by 1-2 large
doses of chorionic gonadotropin (mostly LH) to induce
ovulation.
Adverse Effects…? Multiple births…
In men with hypogonadotrophic hypogonadism, both LH
and FSH are given to stim spermatogenesis and
androgen release.
Testosterone
• ~ 2% of test in plasma is free.
• Converted to dihydrotestosterone (DHT) in skin,
prostate, seminal vesicles, and epididymus.
• Androgen deficiency – treated with i.m. injections
of testosterone propionate.
• Effects: At puberty  2° sexual characteristics in
male.
– In adult male, large doses  gonadotrophin release
and atrophy of interstitial tissue and tubules (testes).
– In women, androgens  changes seen in prepubertal
males.
Estrogens
• The main estrogen released by the ovary.
• Synthetic estrogens may be more effective following
oral administration.
• Adverse Effects (see below, oral contracep):
- prolonged administrations  abnormal endometrial
hyperplasia, abnormal bleeding patterns, assoc with
incr incidence of endometrial cancer.
- But this cancer can be prevented it progestogen
accompanies the estrogen.
- Thus, women taking HRT must also take a
progestogen unless they have had a hysterectomy.
Progestogens
• Used for hormonal contraception and for
producing long-term ovarian suppression for
other purposes (e.g., dysmenorrhea,
endometriosis, hirsutism and bleeding
disorders) when estrogens are contraindicated
Oral Contraceptives
• Uses: Contraception, menstrual irregularities.
• Adverse Effects: hypertension, diabetes, high
LDL, dizziness, numbness, weight gain, fluid
retention, breast tenderness, breakthrough
bleeding.
• Contraindications: ABSOLUTE:
Thromboplebitis, CVA, breast cancer,
pregnancy, liver disease or impairment, CAD, >
35, smoker.
Oral Contraceptives
• Combination Pills – contain estrogen:
ethinylestradiol and progestogen, taken for ~
21 days and discontinued for the following 6-7
days to allow menstruation to occur.
• Progestogen-only Pills – contain low dose of
progestogen, taken continuously.
Fertilization
Copyright © 2010 Pearson Education, Inc.
Oral Contraceptives - Mechanism
• Combination pills act by feedback inhibition on the
hypothal to supress GnRH and hence plasma
gonadotropin secretion.
• Produce an endometrium that is unreceptive to
implantation.
• Alter ovaduct motility.
• Change the composition of cervical mucous.
• These latter effects also caused by progestogen-only
pills and appear to be the basis of their contraceptive
actions.
• Block ovulation in only ~ 25% of women.
• Menstruation often stops initially with progestogens,
but usually returns with prolonged use.
• But the length and duration of bleeding – highly
variable.
Oral Contraceptives
• Combination of both E and P – most potent and
effective way to suppress GnRH, LH, and FSH
secretion.
• The combined effects on previous slide  >99%
efficacy.
• Ethinyl estradiol or mestranol – the E in the
combination contraceptives.
• The progestins – all are potent PR agonists, but
also have some androgenic cross-reactivity.
Norgestrel and levonorgestrel > norethindrone
and norethindrone acetate > ethynodiol,
norgestimate, gestodene, and degestrel in
androgenic activity.
Oral Contraceptives
3 Delivery systems are available: vaginal ring,
transdermal patches, oral tablets.
Ring contains ethinyl estradiol and a progestin,
etonogestrel.
Has zero-order p’kinetics over 21 days.
Dermal patch has ethinyl estradiol and a
progestin, norelgestromin. – Changed weekly
for 3 weeks.
Oral Contraceptives – Adverse Effects
Non-life Threatening
• Breakthrough bleeding and irregular menses (most
women who take combo pills).
• Abdominal pain
• Chest pain, cough, dyspnea, dizziness, numbness,
headache, nausea, changes in libido, breast soreness.
• Eye problems: vision loss or blurred.
• Severe leg pain (calves, thighs).
• Hirsutism, vaginal yeast infections and depression.
• ~ 20-30 % women experience some of these effects.
Oral Contraceptives – Adverse Effects Serious
• Rare.
• Cholestatic jaundice and thromboembolic disease.
• Thromboembolism (~ 25/10,000 women).
Emergency (morning-after) Contraception –
levenorgestrel – a single high dose can be taken up to 3
days after unprotected intercourse. Blocks the LH
surge.
Therapeutic Termination of Pregnancy – mifepristone – a
progesterone ant – highly effective in terminating early
pregnancy (up to 63 days’ gestation) when used with a
PG-cervical ripening agent (e.g., gemeprost pessaries).
[Recall – Progesterone supports endometrial
implantation of fertilized ovum].
-Main adverse effect: pain and bleeding.
Male Contraception
• Tried suppressing sperm production.
- Very unsuccessful.
- Most promising to date: testosterone enanthate
+ daily oral levonorgestrel; and parenternal
ptestosterone undecanoate + injectable
medroxyprogesterone ascetate. But,…
- Highly variable results from clinical trials  only
~ 60% of men became azoospermic.
Significant adverse effects: acne, weight gain,
polycythemia, potential increase in prostate size.
• “back to the drawing board…”
Infertility Drugs
• Example: Clomid
• Stimulates secretion of FSH and LH, which
stimulates maturation of follicles, ovulation
and development of the corpus luteum.
• Uses: Inadequate ovulation, low sperm count
in males.
• Adverse Effects: Similar to those of OCPs.
Increased incidence of early abortion and
multiple births, pelvic pain.
Oxytoxics
• Examples: Pitocin (oxytocin)
• Enhances contractile activity of the uterine
smooth muscle.
• Adverse Effects: Uterine rupture, fetal hypoxia
or trauma, hypertension, CVA.
• Uses: Post-partum hemorrhage only.
Premature Labor Inhibitor
• Examples: Yutopar (rotodrine)
• Selective β2 adrenergic receptor antagonist
that prevents smooth muscle contractions.
• Uses: Preterm labor if gestation > 20 weeks.
• Adverse Effects: palpitations, tachycardia,
hypotension.
Male Hormones
• Example: Testosterone
• Secreted by the testes.
• Uses: Treatment of low sperm count and impotence caused
by any kind of deficiency.
Undescended testicles.
Anabolic action in conditions such as osteoporosis, anemia,
and debilitated states. Inoperable breast cancer in
postmenopausal women.
Adverse Effects: Edema, acne, hirsutism, voice deepening,
polycythemia, increased LDL, depression.
Contraindications: Pregnancy, prostate cancer, breast cancer
in males.