Sex Hormones and Drugs

Hypothalamus

AP

GnRH

Hypothalamic-Pituitary-Gonadal Axis (HPG):

Females

LH surgeTonic LH

Progesterone

PGF2a

Estrogens

+

FSH

Estrogen

LH

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

Sertoli cells

Leydig cells

Hypothalamic-Pituitary-Gonadal Axis (HPG): Males

Hypothalamus

AnteriorPituitary

GnRH

Inhibin

-

-

-

Seminferous tubules:(Spermatogenisis)

Male characteristicsGrowthBehavior: Libido, aggression

+

+

Testosterone

Testosterone

LHFSH

+

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 tissue-

specific.

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 AntagonistsFlutamide and spironolactone – used to treat metastatic

prostate cancer and BPH.Progesterone Receptor AntagonistsMifepristone (aka RU-486) – used to induce 1st-trimester

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 ProgesteroneExample: 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.

InfertilityClomifene 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 contra-indicated

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

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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 EffectsNon-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.