Exam 1 - 508: Fertility

Learning Objectives

• Explain the general pathophysiologic principles of female and male infertility

• Describe potential medication causes of infertility for men and women

• Integrate the pathophysiology of male and female infertility with pharmacologic treatments

• Review an in vitro fertilization treatment schedule

What is the definition impaired fecundity?

Physical difficulty getting pregnant or carrying to live birth

What is defined as infertility?

Inability to conceive after 12 months of unprotected intercourse

OR

6 months of unprotected intercourse if age ≥ 35

What are the two types of infertility?

• Primary infertility: no previous pregnancies

• Secondary infertility: patient has had a previous pregnancy

What are the mechanisms of male fertility?

• Spermatogenesis

• Sperm function

  • Sperm motility

  • Sperm morphology

• Semen production/ transport

  • Blockages

• Ejaculation

  • ED, Retrograde

Any dysfunction in one of these areas can cause male infertility

HPT Axis

• Pituitary hormone effect:

  • LH and FSH stimulate spermatogenesis and testosterone secretion by the testes

• Testes hormone effect:

  • Testosterone and inhibin inhibit the secretion of GnRH by the hypothalamus and LH and FSH by the pituitary

Differentiate primary and secondary causes of impaired spermatogenesis?

• Primary → Impairment of the testes

  • Issues with sertoli cells

  • Issues with Leydig cells

• Secondary → Impairment with the hypothalamus or anterior pituitary

  • Hypothalamic hypogonadism

  • Pituitary insufficiency

  • Hyperprolactinemia

Which medications have a direct toxic effect in causing male infertility?

Alcohol

Illiit medications

Antibiotics (nitrofurantoin, erythromycin)

Antineoplastic agents

Which medications decrease libido? (male infertility)

• Antihypertensives

• Alpha-adrenergic antagonists

• Antipsychotics/ Antidepressants

• Alcohol

Which medications have an indirect toxic effect leading to male infertility?

Calcium channel blockers

Which medications affect the HPT axis, leading to male infertility?

• Anabolic steroids, testosterone (testosterone gel = AndroGel)

• DHEA

• Opioids

• Antipsychotics

• Tricyclic antidepressants

• Spironolactone

• Cimetidine

Does giving testosterone help to increase spermatogenesis and/or aid in male infertility?

No!

• Presence of testosterone negatively feedbacks to the hypothalamus + anterior pituitary to secrete less GnRH and LH + FSH, leading to less sperm production in the testes

How do we treat primary impaired speramtogenesis?

Avoid testosterone

Aromatase inhibitors/SERMs

Assisted reproductive therapy

How do we treat secondary impaired spermatogenesis?

• If hypothalamic source → Pulsatile GnRH

• If pituitary source → GN replacement therapy

W

What role do aromatase inhibitors/SERMs play in treatment of male infertilty

AIs/SERMs help remove the estrogen feedback → Helps to increase testosterone levels

• Aromatase inhibitors → Block conversion of androgens to estrogens

• SERMs increase testosterone levels by blocking estrogen receptors in the brain, stimulating more release of GnRH

What are causes/sources of female infertility?

• 1) Impairment of fallopian tube: absent or blocked

• 2) Impairment of uterine tube: Fibroids or polyps

• 3) Impairment of Cervix: Idiopathic or iatrogenic decrease in receptivity

• 4) Peritoneal: endometriosis, history of PID

What are the WHO groups/classifications of impaired ovulation?

• WHO Group 1: Hypothalamic source

• WHO Group 2: Normogonadotropic, normoestrogenic anovulation

• WHO Group 3: Ovarian source

• WHO Group 4: Others (all other sources of ovulation impairment)

What are characteristics/cause of ovulation impairment in WHO Group 1?

• Hypothalamic source

• Low/normal FSH, low LH, and low estradiol

• Causes: anorexia, malnutrition, chronic/severe stress

What are characteristics/cause of ovulation impairment in 2?

• Normogonadotropic, normoestrogenic anovulation (lack of ovulation despite normal gonadotropins and estrogen levels)

• Normal FSH, Normal/high LH, and Normal estradiol

• Causes: PMOS (formerly PCOS)

What are characteristics/cause of ovulation impairment in WHO group 3?

• Ovarian source

• Low estradiol, High FSH, Normal LH

• Causes: Primary ovarian insufficiency

What are characteristics/cause of ovulation impairment in WHO group 4?

• “Other” category

• Normal/low FSH, Normal LH, and Low estradiol

• Causes: Hyperprolactinemia, thyroid abnormality, congenital adrenal hyperplasia

Which medications are known to affect the HPO axis (hypothalamus-pituitary-ovary)?

Antipsychotics

Antiepileptics

Which medications are known to decrease ovulation?

NSAIDs

Which medication is known cause changes to the cervical mucus?

Clomiphene citrate

What is the most common cause of anovulatory infertility?

Polyendocrine Metabolic Ovarian Syndrome (PMOS, aka PCOS)

What are causes/risk factors for PMOS?

• Genetics

• Epigenetics

• Lifestyle

• Black/Asian/Hispanic women are under-represented in the PMOS literature

What are symptoms of PMOS?

• 1) Hyperandrogenism

  • Acne, facial hair, weight gain, scalp hair loss

  • Most common

• 2) Menstrual disturbances

  • Very infrequent ovulation, in some cases, no ovulation at all

• 3) Metabolic issues

  • Increased risk of DM and CV events

What is the pathophysiology of PMOS?

1. Rapid pulsing of GnRH causes hypersecretion of LH

2. LH stimulates release of androgens. FSH would normally promote conversion of androgens to estrogens. In PCOS this process is inactive.

3. Production and release of androgens → increased inhibin → suppressed FSH → increased androgens

4. Insulin resistance exacerbated by increased androgens → compensatory hyperinsulinemia. Hyperinsulinemia increases androgens by decreasing SHBG and increases GnRH pulse frequency → increased LH secretion

5. Hypothalamus becomes desensitized to ovarian steroids → loss of (-) feedback.

What is the simplified pathophysiology of PMOS?

• Inappropriate gonadotropin secretion (LH) leads to →

• Excessive androgen production, which leads can to →

• Insulin resistance

• And these all feedback/impact eachother

What are non-pharmacologic options for treating PMOS?

• Diet and exercise

  • Reduction in CV risk and metabolic complications

  • Often insufficient to reduce weight, or metabolic or endocrine issues

• Weight loss

  • 5-10% loss associated with restoration of menstrual cycles

  • Reduces testosterone levels

  • May not provide help with hirsutism and acne

  • Pharmacologic interventions often required

What are the two pharmacologic treatment options we can employ?

1) “Override the system” by providing exogenous estrogen/progestin

2) Work on/treat the other physiologic areas impacted by PMOS

• Such as excessive androgen production or insulin resistance

What agents can we give to treat PMOS by providing exogenous estrogen/progestin?

1) Combined oral contraceptives

• Improves acne and hirsutism

• Provides menstrual regularity

• Choose a product with low estrogen and low androgen progestin

• DO NOT GIVE TO PATIENTS WHO DESIRE TO BE PREGNANT

2) Intermittent progestins (medroxyprogesterone)

• Given for 10-14 days at least every 3 months

• Creates withdrawal bleeding

• Reduces risk of endometrial cancer

• No effect on androgen excess

• Can give to patients who wish to get pregnant if timed correctly

Which medication is used to treat excessive androgen production in PMOS?

Spironolactone

• Antiandrogen

• Improved acne and hirsutism

• No effect on menstrual regularity

DO NOT GIVE TO PATIENTS WHO DESIRE PREGNANCY

What do we give to treat insulin resistance in PMOS?

Metformin (Glucophage/Glumetza)

• Improves menstrual regularity/ovulation

• Improves acne and hirsutism

• May help with weight loss

Recent, GLP-1 RAs have been on the rise, however, there is not enough data to support the safety/use in PMOS

What are the goals of ovulation induction?

• Goals:

  • Monofollicular development (development of one egg)

  • Start with the least invasive and simplest treatment option (usually oral)

  • Minimize the risk of ovarian hyperstimulation syndrome (OHSS)

What are our oral agents used for ovulation induction?

• Clomiphene citrate

  • Selective estrogen receptor modulator (SERM)

  • MOA: Down regulates estrogen receptors

  • 50 mg daily x 5 days

  • Dose increased by 50 mg per cycle if ineffective

• Letrozole

  • Aromatase inhibitor (AI)

  • 2.5 mg daily x 5 days

  • Or anastrazole

What are our injectable ovulation induction agents?

• Gonadotropins

  • LH/FSH combination

  • FSH

• Human chorionic gonadotropin (hCG)

  • Injected in a single dose to simulate LH surge mid-cycle

  • Finalizes follicular development

    • Ovulation expected in ~ 24 hrs

    • Timed with intercourse/intrauterine insemination (IUI)

  • Most often used with gonadotropins, but can also use with oral OI agents

What role does hCG have as an ovulation inducing agent?

hCG creates the LH surge

What role do gonadotropins have as an ovulation inducing agent?

Stimulate follicle growth

What are potential adverse effects of using ovulation induction agents?

• Multiple gestations (multple babies)

  • Risk of prematurity, LBW, miscarriage, gestational diabetes, preeclampsia

  • Prevent with step up dosing

  • Stop OI if >2 mature follicles

  • Highest risk with gonadotropins (36%)

• Serious

  • Ovarian hyperstimulation syndrome

  • Risk minimized by monitoring follicle development

  • Sequential transvaginal ultrasounds

  • Serum estradiol levels

What is ovarian hyperstimulation syndrome (OHSS)?

• An exaggerated, systemic reaction to excess fertility hormones that causes the ovaries to swell and fluid to leak into the abdominal cavity (Most commonly seen with gonadotropins)

• Potentially fatal “3rd spacing” of intravascular fluid

  • Mild: abdominal discomfort, N/V/D

  • Severe: ascites, pleural effusion, oliguria, hemodynamic instability

• Prevention: low doses, step-up therapy, close monitoring and withholding trigger dose

What is assisted reproductive technology (ART)?

Most commonly used is in vitro fertilization

• “IVF” commonly used for all ART

• Manipulation of oocytes and sperm

• Medications are utilized to

  • Stimulate multiple follicles for oocyte retrieval

  • Optimize implantation after embryo transfer

Limiting factor → COST (no universal insurance coverage)

When is assisted reproductive technology used?

• History of failed ovulation induction with or without intrauterine insemination

• Structural factors (i.e. blocked fallopian tubes)

• Male factor issues (infertility)

What is controlled ovarian hyperstimulation?

The monitored use of ovulation induction agents to create several follicles for IVF

Which medications do we use in stage 1: Controlled ovarian hyperstimulation (COHS)

1) Oral contraceptives

• Control onset of menses and the start of COHS

2) GnRH agonists or antagonists

• Prevent premature LH surge or disruption of COHS

3) Gonadotropins (FSH or FSH + LH)

• Stimulates development of multiple ovarian follicles for oocyte retrieval

Which medications do we use in stage 2: Oocyte retrieval?

hCG (or GnRH agonists)

• Role: They induce folliculat development/maturation for oocyte retrieval

Which medications do we use in stage 3: Luteal phase support?

Progesterone

• Role: maintain endometrium for embryo transfer and implantation

What role do GnRH agonists have?

GnRH agonists first stimulate, then down regulate FSH/LH production

What role do GnRH antagonists have?

GnRH antagonists down regulate without having initial stimulation

What AEs are associated with GnRH agonists/antagonists?

Headaches

Hot flashes

Edema

Abdominal pain