Drug Treatment of Infertility

Normally sequence of events start from hypothalamus with gonadotropic releasing hormones acting on gonadotropic cells of pituitary to cause release of gonadotropins, which move downwards to ovary and tetes to stimulate them, causing secretion of estrogen and progesterone. Thus hypothalamus hypophyseal axis is formed.

Any disturbance can lead to infertility, drugs act at different levels:

Drugs Affecting Gonadotropic Releasing Hormones

• GnRH analogs/agonists
• GnRH antagonists

GnRH & its analogs

Pulsatile release occurs which can suppress release of gonadotropins

• Gonadorelin
• Goserelin
• Leuprolide
• Nafarelin

When need for stimulation given by special pumps every 90 mins in pulses

Female Infertility

•             Stimulation of gonadotropins – LH surge, given in pulses
•             Suppression of gonadotropins
•             Suppress premature LH surge, administered in continuous manner
•             Controlled ovarian hyperstimulation – Assisted Reproductive Technique

Male Infertility

• Hypothalamic-hypogonadotropic hypogonadism
• Pulsatile – 3- 6 minutes

GnRH antagonists

• Genirelix
• Cetrorelix

Same effect as GnRH analogs given in continuous dose.

• Suppression of gonadotropins
• Suppress premature LH surge
• Controlled ovarian hyperstimulation –ART

Advantage – immediate action as antagonists to receptors inhibit directly in the cells of pituitary

                      – short duration of treatment

Disadvantage – suppression of ovarian hormones

Gonadotropins

3 types:

a.      FSH
b.      LH
c.       hCG

Different preparations are available:

•       Menotropin (hMG) – FSH+LH
•       FSH – Urofollitropin (uFSH)
•                 – Follitropin alfa & beta (rFSH)
•       LH –   Lutropin alfa (rLH) (recombinant DNA technology)
•       hCG – hCG (human urine of pregnant females)

                            – Choriogonadotropin alfa (rhCG)

Male Infertility

• Used in patients of Hypogonadotropic hypogonadism
•  Androgens –development of sexual characters
• hCG  (steroidogenesis)
  
• hMG / rFSH required for spermatogenesis    

Female Infertility

Used for Induction of ovulation

Protocol

•             hMG / rFSH (7-12 days)
•             continuous monitoring by Serum E / USG – when follicles >18mm:
•             GnRH agonist / antagonist to suppress premature LH surge
• When follicles prepared, single dose of hCG leading to ovulation
• Insemination / oocyte retrieval for ART
• Luteal support

Adverse effects

1.             Multiple pregnancies
2.             OHSS
3.             Increased vascular permeability leading to ascities
4.             Pleural effusion, pericardial effusion
5.             Oliguria, shock, thromboembolism

Clomiphene

•       Ovulation inducing agent
•       Partial estrogen agonist (SERM)

Pharmacokinetics

• Given orally 100 mg/day
• Half life is 5-7 days
• Extensive PPB.
• Also undergoes enterohepatic circulation
• Mainly excreted in urine.

Mechanism of Action and Pharmacological effects

•             As parital agonist inhibits estrogenic feedback to pituitary causing release of GnRH / Gonadotropins
•             Increased amplitude of FSH & LH pulses occurs
  

Therapeutic Uses

1.             Hypothalamic-hypophyseal-ovarian system has to be intact for drug to act.
2.             Ovulation induction – 100 mg/day for 5 days for one cycle

                                                                   – Upto 12 cycles

Adverse effects

1.             Multiple pregnancies
2.             OHSS
3.             Intensification & prolongation of afterimages
4.             Ovarian cancer
5.             Hot flushes / headache / constipation / allergic skin reaction / reversible hair loss

Bromocriptine

–        Semisynthetic ergot alkaloid

–        D₂ receptor agonist

–        Used for Hyperprolactinemia

–        Known to cause amenorrhea / Infertility

Progesterone

Luteal support in assisted reproductive technique.