Drugs used in gonads disorders

Dr.Hazar

Objectives

After studying this unit, you should be able to:

1. Recall the physiological actions of male and female sex hormones

2. List the drugs and mechanisms used to attenuate the actions of sex hormones and their clinical uses in different gonadal disorders

3. Discuss the most current data relating to the action ,uses , adverse affects and contraindication of estrogen replacement therapy. HRT

Outline-topics to be discussed-

• Hormone physiology,Ovulation,Hormone regulation and cycling

• Gonadotrophines , Gonadotrophines Analogues• Androgens and antiandrogens• Bromocriptine & Analogues• Estrogen , progesterone ,agonists and antagonists • Drugs acting on the uterus• SERMs (selective estrogen receptor modulators)• Contraceptives• Infertility

Hormone physiology,Ovulation,Hormone regulation and cycling

Female Reproductive Anatomy and Physiology: Overview

• Ovary• Fallopian tube• Uterus

– Cervix– Endometrium

• Vagina– Clitoris

– Labia

• Follicle• Oocytes• Granulosa cells

– Estrogen– Corpus luteum

• Corpus luteum– Progesterone

Menstrual Cycle: Ova Maturation, and Endometrial Growth

• Follicular phase– Egg matures

• Ovulation– ovum released

• Luteal phase– Corpus luteum– Endometrium – Prep for blastocyst

• No Pregnancy– Menses

Neuroendocrine Control of Menstrual Cycle:

Hormonal control of the female reproductive system

• The menstrual cycle starts with menstruation. • Gonadotrophin-releasing hormone, released from the hypothalamus, acts on the

anterior pituitary to release follicle-stimulating hormone (FSH) and luteinising hormone (LH).

• FSH and LH stimulate follicle development in the ovary. FSH is the main hormone stimulating oestrogen release. LH stimulates ovulation at mid-cycle and is the main hormone controlling subsequent progesterone secretion from the corpus luteum.

• Oestrogen controls the proliferative phase of the endometrium and has negative feedback effects on the anterior pituitary. Progesterone controls the later secretory phase, and has negative feedback effects on both the hypothalamus and anterior pituitary.

• If a fertilised ovum is implanted, the corpus luteum continues to secrete progesterone.

• After implantation, human chorionic gonadotrophin from the chorion becomes important, and later in pregnancy progesterone and other hormones are secreted by the placenta.

Follicular and luteal Phases

• FSH stimulates follicular development

• Estrogen: - feedback, limits more follicles

• LH stimulate corpus luteum development

• Progesterone

Gonadotrophines , Gonadotrophines Analogues

Gonadotrophines (LH &FSH ) & Analogues

Gonadotrophines , Gonadotrophines Analogues & Clinical uses

The following are LH & FSH drugs

1. Follitropin α -Recombinant human FSH.

2. Follitropin β -Recombinant human FSH.

3. Lutropin α -Recombinant human LH.

4. Choriogonadotropin α -Recombinant HCG.

5. Follitropin -FSH

6. HumanMenopausalgonadotrophin -LH&FSH

No 5&6 are made from purified extract of human Menopausal urine.

Gonadotrophines , Gonadotrophines Analogues & Clinical uses

• LH &FSH are used in Infertility.A-Female Infertility 1.Caused by lack of ovulation as a result of

Hypopituitarism or failure of treatment with Clomiphene.

2.Induction of ovulation IVF which is InVitro fertilisation(Infertility is caused by

mechanical obstruction of the fallopian tubes).-Monitor to avoid ovarian hyperstimulation

→multiple pregnancy

Male infertility

Oligospermia (associated with hypopituitarism + Anosmia).

• HCG

In boys with Delayed puberty (Testosterone is preferred ).

Androgens and antiandrogens

Androgens and the hormonal control of the male reproductive system

• LHRH (GnRH) from the hypothalamus acts on the anterior pituitary to release both follicle-stimulating hormone, which stimulates gametogenesis, and LH (also called interstitial cell-stimulating hormone), which stimulates androgen secretion.

• The endogenous hormone is testosterone; intramuscular depot injections of testosterone esters are used for replacement therapy.

• Mechanism of action is via intracellular receptors. • Effects depend on age/sex, and include development of

male secondary sexual characteristics in prepubertal boys and masculinisation in women.

Clinical use of androgens and antiandrogens

• Androgens (testosterone preparations) as hormone replacement in: – male hypogonadism due to pituitary or testicular

disease (e.g. 2.5 mg/day patches) – Female hyposexuality following ovariectomy (e.g.

300μg/day patches). • Antiandrogens (e.g. flutamide,

cyproterone,bicalutamide) are used as part of the treatment of prostatic cancer.

• 5α-Reductase inhibitors (e.g. finasteride) are used in benign prostatic hypertrophy.

Aromatase Inhibitors

ERECTILE DYSFUNCTION

• Erectile function depends on complex interactions between physiological and psychological factors. Erection is caused by vasorelaxation in the arteries and arterioles supplying the erectile tissue. Innervations of the penis includes autonomic and somatic nerves.

• Nitric oxide is probably the main mediator of erection and is released both from nitrergic nerves and from endothelium .

• Erectile function is adversely affected by several therapeutic drugs (including many antipsychotic, antidepressant and antihypertensive agents),. There are several organic causes, including hypogonadism ,hyperprolactinaemia , arterial disease and various causes of neuropathy (most commonly diabetes).

PHOSPHODIESTERASE TYPE V INHIBITORS

• Sildenafil, the first selective phosphodiesterase type V inhibitor , was found incidentally to influence erectile function.

• Tadalafil and vardenafil are also phosphodiesterase type V inhibitors licensed to treat erectile dysfunction. Tadalafil is longer acting than sildenafil.

 

Mechanism of action

• Phosphodiesterase V is the isoform that inactivates cGMP. Nitrergic nerves release nitric oxide (or a related nitrosothiol), which diffuses into smooth muscle cells, where it activates guanylate cyclase. The resulting increase in cytoplasmic cGMP mediates vasodilation via activation of protein kinase G .

• Consequently, inhibition of phosphodiesterase V potentiates the effect on penile vascular smooth muscle of endothelium-derived nitric oxide and of nitrergic nerves that are activated by sexual stimulation.

Side effects

• Many of the unwanted effects of phosphodiesterase type V inhibitors are caused by vasodilatation in other vascular beds; these effects include

• hypotension, • flushing and• headache.• Visual disturbances have occasionally been reported and are of

concern because sildenafil has some action on phosphodiesterase VI, which is present in retina and important in vision. The manufacturers advise that sildenafil should not be used in patients with hereditary retinal degenerative diseases (such as retinitis pigmentosa) because of the theoretical risk posed by this. Vardenafil is more selective for the type V isozyme than is sildenafil , but is also C.I in patients with hereditary retinal disorders

C.I

• Pigmentary Retinopathy, Eye Disease Caused by, Pulmonary Veno-occlusive Disease, Hearing Loss, Severe Uncontrolled High Blood Pressure, Heart Attack, Unpredictable Severe Constricting Chest Pain, Narrowing of the Aortic Heart Valve, Idiopathic Hypertrophic Subaortic Stenosis, Life-Threatening Irregular Heart Rhythm, Chronic Heart Failure, Stroke, Abnormally Low Blood Pressure, Severe Liver Disease, Serious Kidney Problems, Leukemia, Problems with Food Passing Through the Esophagus, Sickle Cell Anemia,

Bromocriptine & Analogues

Bromocriptine & Analogues

• Prolactin is secreted from antr.pit. Under the inhibitory effect of PRIF(dopamine).

• Its main function is to control milk production.

Pit. Deficiency → ↓PRL → failure to lactate

Hyp. Destruction → ↑ PRL →Hyperprolactinemia.

-In Men Hyperprolactinemia →Impotance &Gynecomastia.

In women → Galactorrhea & Hypogonadism

Bromocriptine & Analogues

• Bromocriptine is a dopamine agonist (D2-R)

↓PRL used in :

1.Parkinsons .

2.Acromegaly.

3.Prolactinomas.

4.Galactorrhea.(hyperprolactinemia)

5.Benign breast diseases.

6.Suppression of lactation

Analogues

1-Cabergoline

M.O.A like Bromocriptine but longer duration of action ,better tolerated & used to inhibit lactation.

2.Quinagolide

M.O.A . like Bromocriptine but S.E. hypotension used only in hyperprolactinemia

Estrogen , progesterone ,agonists and antagonists

Oestrogens• The endogenous oestrogens are oestradiol (the most potent), oestrone and

oestriol; there are numerous exogenous synthetic forms (e.g. ethinylestradiol).

• Mechanism of action involves interaction with nuclear receptors (termed ERα or ERβ) in target tissues, resulting in modification of gene transcription.

• Their pharmacological effects depend on the sexual maturity of the recipient:

– before puberty, they stimulate development of secondary sexual characteristics

– given cyclically in the female adult, they induce an artificial menstrual cycle and are used for contraception

– given at or after the menopause, they prevent menopausal symptoms and protect against osteoporosis, but increase thromboembolism.

• Antioestrogens are competitive antagonists or partial agonists. Tamoxifen is used in oestrogen-dependent breast cancer. Clomiphene induces ovulation by inhibiting the negative feedback effects on the hypothalamus and anterior pituitary.

• Selective drugs that are oestrogen agonists in some tissues but antagonists in others are being developed. Raloxifene (SERM) is used to treat and prevent osteoporosis.

Clinical uses of oestrogens and antioestrogens

• Oestrogens Replacement therapy: – - primary ovarian failure (e.g. Turner's syndrome) – - secondary ovarian failure (menopause) for flushing,

vaginal dryness and to preserve bone mass. • Contraception. • Prostate and breast cancer (these uses have largely

been superseded by other hormonal manipulations.• Antioestrogens To treat oestrogen-sensitive breast

cancer (tamoxifen). • To induce ovulation (clomiphene) in treating infertility.

Synthetic steroids

Used in oral contraceptives Inactive prodrug metabolized

in the liver (demethylated)

Breast cancer

• ↑Estrogen →↑breast proliferation→↓ TGF- β • Progression of malignancy is associated with

↓ level cytokines transforming growth factor β (TGF- β ).

• Tamoxifen→ ↓Estrogen →↑↑ TGF- β • side effects- 1.nausea, vomiting, hot flashes, menstrual

irregularities, cataracts. 2.Increase in endometrial cancer (2-fold).

Oestrogen receptor antagonists

fulvestrant

Monthly IM injection

“for hormone receptor-positive metastatic breast cancer in postmenopausal women whose breast cancer has recurred or progressed following antiestrogen therapy.”

Used to treat tamoxifen resistant breast cancer

Tormifene

Used in estrogen –sensitive breast cancer.

Aromatase Inhibitors

Aromatase Inhibitors

1-FormastaneAs effective as tamoxifen, but don’t increase uterine

cancer treatment for breast cancer2 -Letrozole Mainly used as adjuvant therapy for post-menopausal

women with ER+ early stage breast cancer & for metastatic breast cancer

Not for premenopausal women3-Anastrozole

Used for the treatment of postmenopausal breast cancer

4-Exemestane in treatment for breast cancer

Progesterone

Progesterone• In the ovary, progesterone is produced by the corpus

luteum ,circulating levels are highest in luteal phase of cycle.

• Stimulates the development of the uterine endometrium and vagina

• Important in the maintenance of pregnancy. • Suppresses menstration and uterine contractility &

Stimulates lactation. • Complement the action of estrogen on primary and

secondary sex characteristics

Progestogens (progestins) and antiprogestogens

• The endogenous hormone is progesterone. Examples of synthetic drugs are the progesterone derivative medroxyprogesterone and the testosterone derivative norethisterone.

• Mechanism of action involves intracellular receptor/altered gene expression, as for other steroid hormones. Oestrogen stimulates synthesis of progesterone receptors, whereas progesterone inhibits synthesis of oestrogen receptors.

• Main therapeutic uses are in oral contraception and oestrogen replacement regimens, and to treat endometriosis.

• The antiprogestogen mifepristone, in combination with prostaglandin analogues, is an effective medical alternative to surgical termination of early pregnancy.

Clinical uses of progestogens and antiprogestogens

• Progestogens • Contraception:

– - with oestrogen in combined oral contraceptive pill – - as progesterone-only contraceptive pill – - as injectable or implantable progesterone-only contraception – - as part of an intrauterine contraceptive system.

• Combined with oestrogen for oestrogen replacement therapy in women with an intact uterus, to prevent endometrial hyperplasia and carcinoma.

• For endometriosis. • In endometrial carcinoma; use in breast and renal cancer has declined. • Poorly validated uses have included various menstrual disorders. • Antiprogestogens Medical termination of pregnancy: mifepristone

(partial agonist) combined with a prostaglandin (e.g. gemeprost).

Types of Progestogens

Many are used as oral contraceptives:1.Progesterone & analogues. Dydrogesterone ,Gestronol , Megestrol

Medroxyprogesterone.2. Testosterone analogues Norethindrone , Norgestrel , Ethynodiol .3.Derivative of Norgestrel levonorgestrel,Desogestrel and Norgestimate Gestadone. However , Desogestrel and Gestadone are

associated with higher risk of venous thromboembolism.

Adverse effects

• may reduce plasma HDL • *venus thromboembolism• weight gain( fluid retension )• Depression• Acne• menstrual irregularities

Antiprogestogens

Mifepristone

• Partial agonist at progesterone receptor in the uterus and sensitize the uterus to the action of PG

• Progesterone is required for the maintenance of early pregnancy

• High amounts induce prostaglandin F2, leading to abortion and is used with Gemeprost as a medical alternative to surgical termination of pregnancy

Drugs acting on the uterus

Drugs acting on the uterus• At parturition, oxytocin causes regular coordinated uterine

contractions, each followed by relaxation;• Ergometrine, an ergot alkaloid, causes uterine contractions

with an increase in basal tone. • Atosiban, an antagonist of oxytocin , delays labour. • Prostaglandin (PG) analogues, for example dinoprostone

(PGE2) and dinoprost (PGF2α), contract the pregnant uterus but relax the cervix. Cyclo-oxygenase inhibitors inhibit PG synthesis and delay labour. They also alleviate symptoms of dysmenorrhoea and menorrhagia.

• The β2-adrenoceptor agonists (e.g. ritodrine) inhibit spontaneous and oxytocin-induced contractions of the pregnant uterus

Clinical uses of drugs acting on the uterus

• Myometrial stimulants (oxytocics)• Oxytocin is used to induce or augment labour when the uterine muscle is not

functioning adequately. It can also be used to treat postpartum haemorrhage.

• Ergometrine can be used to treat postpartum haemorrhage. Carboprost can be used if patients do not respond to ergometrine.

• A preparation containing both oxytocin and ergometrine is used for the management of the third stage of labour; the two agents together can also be used, prior to surgery, to control bleeding due to incomplete abortion.

• Dinoprostone given by the extra-amniotic route is used for late (second trimester) therapeutic abortion; given as vaginal gel, it is used for cervical ripening and induction of labour.

• Gemeprost, given as vaginal pessary following mifepristone , is used as a medical alternative to surgical termination of pregnancy (up to 63 days of gestation).

• Myometrial relaxants• The β-adrenoceptor agonists (e.g. ritodrine) are used to delay preterm labour.

• Atosiban (oxytocin antagonist) also delays preterm labour

Menopause -HRT

• At the menopause, whether natural or surgically induced, ovarian function decreases and oestrogen levels fall. There is a long history of disagreement regarding the pros and cons of hormone replacement therapy (HRT) .

• HRT normally involves the cyclic or continuous administration of low doses of one or more oestrogens, with or without a progestogen.

• Short-term HRT has some clear-cut benefits:

-improvement of symptoms caused by reduced oestrogen, for example hot flushes and vaginal dryness

-prevention and treatment of osteoporosis, but other drugs are usually preferable .

• Oestrogen replacement does not reduce the risk of coronary heart disease, despite earlier hopes, nor is there evidence that it reduces age-related decline in cognitive function.

• Drawbacks include:

• cyclical withdrawal bleeding

• adverse effects related to progestogen

• increased risk of endometrial cancer if oestrogen is given unopposed by progestogen

• increased risk of breast cancer, related to the duration of HRT use and disappearing within 5 years of stopping

• increased risk of venous thromboembolism (risk approximately doubled in women using combined HRT for 5 years).

• Oestrogens used in HRT can be given orally (conjugated estrogens, estradiol, estriol), vaginally (estriol), by transdermal patch (estradiol) or by subcutaneous implant (estradiol).

Partial agonists

1-Raloxifene (SERM)• Used to prevent fractures in postmenopausal at risk of

Osteoporosis• No effect on Vasomotor symptom 2- Tibolone is marketed for the short-term treatment of symptoms of

oestrogen deficiency.• Combine activities of estrogenic , progestagenic and a weak

androgenic activities. and can be used continuously without cyclical progesterone (avoiding the inconvenience of withdrawal bleeding).

• For Vasomotor symptom & Osteoporosis prophylaxis

Osteoporosis

OsteoporosisBone mineral homostasis:• Ca & Po4 , are major mineral constituents of bones.• PTH & vit.D are primary regulators.• Secondary regulators( Calc., Glucocort., estrogens)• Bones provide structural support & hematopoiesis.

Natural Estrogens↓ bone resorption by:

1.Antagonizing the effect of PTH & interlukin-6 on bones but but it does not ↑bone formation .

2.Promoting apoptosis of oesteoclasts.

Antiresorptive drugs for oesteoporosis :

1.Bisphosphonates

alendronate, risedronate, ibandronate, etidronate

2.SERMs (Selective estrogen receptor modulators)ex. Raloxifene

3.Estrogen.

4.Calcitonin

Pro’s and Con’s of Available Osteoporosis Therapies

Agent Pro’s Con’s

• Calcium/Vit D Cheap, accessible Partial efficacy

• HRT Effective breast ca, DVT, MI

• Raloxifene vert Fx, breast ca?•• Bisphosphonates vert and nonvert Fx GI intolerance

• Teriparatide Effective Expensive, daily injections

•