Estrogens and Progestins: Basic Pharmacology and Common Applications

The Menstrual Cycle  First half – follicular phase  Second half – luteal phase Role of : ovary and uterus estrogen and progesterone

Hypothalmus GnRH Anterior Pituitary LH FSH ↑ ova production maturation ovulation ovaryovary Increases progesterone Negative Feedback Loop stopping GnRH ↑ Estrodiol levels Negative feedback loop stopping FSH Corpus luteum The Menstrual Cycle And Gonadotropin Hormones

Estrogen In premenopausal women, estrogen is produced in the ovaries primarily and small amount in adrenal cortex. Major estrogen produced - Estradiol (most potent) Estrogens support the development and maintenance of the female reproductive tract and secondary sex characteristics In males, small amounts of testosterone are converted into estradiol by the testes

Metabolic Actions of Estrogen Bone – estrogens have a positive effect on bone mass Plasma Proteins- increase production of transport proteins for thyroxine, estrogen, testosterone Cholesterol - estrogens have favorable effect on cholesterol  LDL  HDL Blood coagulation – both promote and suppress coagulation

Therapeutic Uses Birth Control Hormone therapy after menopause Female hypogonadism Availability – oral, transdermal, intravaginal, parenteral

Adverse Effects Endometrial hyperplasia & carcinoma Breast cancer Ovarian cancer CV events Nausea & other GI disturbances

Progestins Principal endogenous hormone – secreted by the corpus luteum, placenta and adrenal cortex. Prepare uterus for implantation of fertilized ovum. Circulate in blood attached to a specific plasma protein, metabolized in liver and conjugated for excretion in the bile.

Progestins Primary use of progestins – Counter the adverse effects of estrogen on the endometrium in women undergoing HT and birth control. Uses - Dysfunctional uterine bleeding Amenorrhea Adverse effects – Teratogenic effects Breast cancer Tenderness & bloating Thromboembolic events

Birth Control Is interfering with the reproductive process at any step from gametogenesis to nidation Methods are safe and effective however unwanted pregnancies are common – suggests available methods are not used as much or as effectively as they could be.

Birth Control Pharmacological methods oral contraceptives hormonal implants IUDs vaginal rings transdermal patches Nonpharmacological methods surgical sterilization mechanical devices avoiding intercourse

Oral Contraceptives OCs – 2 nd most widely used form of BC Effectiveness - expressed as the % of accidental pregnancies that occur while using the technique Perfect vs Typical

Birth Control Effectiveness Most effective – subdermal implant, IUD, sterilization Least reliable – periodic abstinence, spermicides, cervical cap Safety - complex to determine OCs as currently prescribed are much safer than when used in the past Must also consider the risk of mortality with pregnancy and delivery

Birth Control Factors to consider when choosing a BC method Effectiveness Safety Personal Preference Use in caution with: women with history of CV disorders women who smoke women over 35 – can use OC but not if they smoke past or current breast cancer, cirrhosis and use of anticonvulsants.

Oral Contraceptives Main categories: 1. contain both estrogen & progestin combination OCs 2. contain only progestin (mini-pills or progestin only OCs) Combination OCs are classified as: 1. monophasic 2. biphasic 3. triphasic 4. quadriphasic

Combination OCs Most widely prescribed Highly effective – nearly 100% (  in overweight women) Very safe Consist of an estrogen plus a progestin M OA inhibition of ovulation; suppress FSH / LH promote thickening of cervical mucous modify the endometrium – less favorable for implantation

Combination OCs Adverse Effects  Thromboembolic disorders  HTN  Cancer  Abnormal uterine bleeding Progestin only OCs Contain progestin but no estrogen  SEs but irregular bleeding Beneficial effects – altering cervical secretions

Contraceptives with novel delivery systems Transdermal patch Vaginal ring Long-acting contraceptives subdermal implants –Nexplanon (good for 3 years) *no longer using Norplant Depo-Provera injections – good for 3 months

Menopausal Hormone Therapy Two basic regimens for HT. 1)Estrogen alone 2)Estrogen plus a progestin Why give estrogen?? Why is progestin necessary??

Research studies Women’s Health Initiative (WHI) Heart and estrogen/progestin replacement study (HERS) Controversial effects on: CV events endometrial cancer breast cancer ovarian cancer colorectal cancer dementia urinary incontinence

Menopausal Hormone Therapy Called HT (hormone therapy) low doses of estrogen ± progestin taken to manage symptoms caused by loss of estrogen that occurs during menopause Why is estrogen lost? Consequences:  vasomotor symptoms (hot flashes, night sweats)  urogenital atrophy  accelerated bone loss

Androgens Androgen hormones produced by the testes, ovaries and adrenal cortex Major endogenous androgen is.. Function to promote expression of male sex characteristics Influence sexuality in females Also, androgens have significant physiologic and pharmacologic effects unrelated to sex

Androgens Primary clinical application - androgen deficiency in males Therapeutic uses  Male Hypogonadism  Delayed puberty Availability oral, IM, transdermal patch & gel, implantable pellets, buccal tablets

Androgens Adverse effects virilization premature epiphyseal closure hepatotoxcity effects on cholesterol levels (  LDL &  HDL) abuse potential

Anabolic steroid use Who uses? athletes of all types and age Why use? increased muscle mass & strength Risks? sterility, gynecomastia, acne,  HDL,  LDL, testicular shrinkage

Transgendered/Transsexual Clients Definitions: Transgendered - state of one’s gender identity not matching one’s assigned sex Transsexual - people have a desire to live and be accepted as a member of the gender opposite to that assigned at birth  Hormonal therapy is an important part of this process  Determination of therapy goals and agents to be used  Risks of hormone therapy, societal pressures, and access to hormones can make this process very challenging

Transgendered/Transexual Clients Goals of Hormonal therapy:  To reduce endogenous hormone levels thereby reducing the secondary sex characteristics of the person’s biological sex.  To replace endogenous sex hormone levels with those of the reassigned sex by using principles of hormone replacement therapy.

Before After

Hormone therapy in transsexual clients MTF transsexual persons 1 Dosage Estrogen Oral: estradiol2.0–6.0 mg/d Transdermal: estradiol patch0.1–0.4 mg twice weekly Parenteral: estradiol valerate or cypionate5–20 mg im every 2 wk 2–10 mg im every week Antiandrogens Spironolactone100–200 mg/d Cyproterone acetate 2 50–100 mg/d GnRH agonist3.75 mg sc monthly FTM transsexual persons Testosterone Oral: testosterone undecanoate 2 160–240 mg/d Parenteral Testosterone enanthate or cypionate100–200 mg im every 2 wk or 50% weekly Testosterone undecanoate mg every 12 wk Transdermal Testosterone gel 1%2.5–10 g/d Testosterone patch2.5–7.5 mg/d.

SERMs What are they? Selective Estrogen Receptor Modulators What is the M OA? Blocks selected estrogen receptors What are the benefits? Provide benefits of estrogen while decreasing drawbacks

Anastrazole (Arimidex®), Exemestane (Aromasin®), Letrozole (Femara®). SERM’s

Take Home Message Do an individualized assessment Determine risk factors; benefit versus risk Do not use estrogen/progesterone for long-term therapy Consider alternative therapies If using, use the lowest dose for the shortest period of time