Reproductive Endocrinology Flashcards

1
Q

organs/brain regions and hormones associated with Hypothalamic-Pituitary-Gonadal Axis?

A
Hypothalamus:
  Gonadotropin Releasing Hormone (GnRH)
Pituitary:
  Follicle Stimulating Hormone (FSH)
  Luteinizing Hormone (LH)
Ovary:
  Estradiol
  Progesterone
Testes:
  Testosterone
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2
Q

What is GnRH? What results from it’s activation?

A

10 aa peptide
Secreted in pulsatile fashion (2-3 hr cycle)
Higher frequency stimulates FSH secretion
Lower frequency stimulates LH secretion
Sexual maturity results from activation of GnRH secretion

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3
Q

Describe FSH and LH. What function do they play in males and females?

A

Heterodimeric glycoproteins
α-subunit – shared by FSH, LH, TSH, and hCG
ß-subunit – provides unique actions of hormones
FSH - MW ~34,000
LH – MW ~28,000
Each have trophic functions in males and females

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4
Q

Describe sexual differentiation in embryos.

A

Up to 8 weeks gestation, embryos contain primordial genital ducts of both sexes:
Wolffian – male
Mullerian – female
At 8 weeks, testes begin production of:
Testosterone – supports development of Wolffian:
Epididymis, vas deferens and seminal vesicles
Anti-mullerian hormone – blocks Mullerian growth:
Fallopian tubes, uterus, upper vagina

Lack of testosterone action leads to Wolffian degeneration and Mullerian development

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5
Q

What happens during female puberty? Adrenarche? Menarche?

A

~400,000 primordial follicles at puberty
300-400 will reach maturity and ovulate
Remainder “die” by atresia throughout life

Puberty:
Adrenarche – onset of adrenal androgen synthesis
Onset at 6-7 years
Androstendione, DHEA and DHEAS
Dec. sensitivity of HP axis to negative feedback
GnRH and gonadotropin secretion
Menarche – onset of menstrual cycles

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6
Q

Describe the Female HPG Axis.

A
GnRH stimulates FSH and LH release
FSH – follicular maturation and estradiol synthesis
LH – follicular rupture and progesterone synthesis
Estradiol (E2)
  Endometrial proliferation
  Pos and neg feedback
Progesterone (P4)
E  ndometrial support
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7
Q

Name two Female hormones and their functions.

A
Estradiol(-17ß) – E2
18 carbon aromatic steroid
Promotes secondary sexual characteristics
Increases HDL, some proteins (eg, TBG)
Synthesized in ovary and placenta
Progesterone – P4
21 carbon steroid
Precursor of many steroids
Some influence on breast development
Primarily involved in pregnancy
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8
Q

How is Estradiol measured?

A

Estradiol
Reference is interval age and menstrual cycle dependent
39-375 pg/mL (follicular phase)
49-440 pg/mL (luteal phase)

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9
Q

How is progesterone measured?

A

Progesterone
Ref. interval is age, cycle & pregnancy stage dependent
0-2.7 ng/mL (follicular phase)
3.0-31.4 ng/mL (luteal phase)
Pregnancy: 11.0-45.0, 26.0-89.0, 46.0-423 ng/mL by trimester
Immunoassay (competitive)
LC-MS/MS

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10
Q

How is Gonadotropin measured?

A

Immunoassay (usually sandwich assays)
Reference ranges sex, age and cycle variable
Ultrasensitive assays available – necessary for prepubertal evaluations

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11
Q

What happens during an LH surge?

A

Release of egg from follicle

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12
Q

What happens during the follicular phase?

A

Late luteal phase (of prev. cycle) E2 and P4 decline, FSH secretion increases (loss of negative feedback)

FSH stimulates follicular proliferation and E2
Day 1-4 – several follicles recruited and develop
Granulosa cells synthesize and secrete E2
Day 5-7 – dominant follicle selected, suppressing others
E2 stimulates endometrial (uterine lining) proliferation
E2 negative feedback suppresses FSH secretion
E2 synthesis continues
Antral follicle is final product

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13
Q

What happens during the ovulatory phase?

A

Rising follicular E2 stimulates LH surge at day 12-13 via positive feedback

LH peaks 24-36 hours later

Ovulation – 10-12 hrs post LH peak (day 14)

  • –Follicular rupture
  • –Ovum release

LH stimulates follicular synthesis of P4
Ovum captured by fallopian tubes

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14
Q

What happens during the luteal phase?

A

Ruptured follicle transforms to corpus luteum
Corpus luteum (CL) synthesizes P4 and E2
-P4 rises ~3 days post ovulation
-P4 suppresses LH and FSH secretion
-P4 peaks about 8-9 days post ovulation
Fertilized ovum implants in uterine lining
-hCG synthesis by trophoblast maintains CL
-CL P4 maintains endometrium
Without hCG, CL begins regression ~day 9
-Decreasing P4 promotes endometrial sloughing

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15
Q

What is menopause?

A

Defined as 12 months of amenorrhea
—Mean age at 51 years
—No correlation with age of menarche
Primary depletion of ovarian follicles
Decreased estradiol (10% of normal levels)
Increased FSH & LH (no negative feedback)
—FSH 10-15x due to longer half-life (4 hrs)
—LH 4-5x (half-life 30 minutes)

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16
Q

Disorders of Female Reproduction.

A

Pseudohermaphroditism:

  • –Gonadal sex different than genital sex
  • –46,XX karyotype with ambiguous genitalia
  • Congenital adrenal hyperplasia (CAH)

Precocious puberty:

  • –Secondary sexual characteristics before age 8
  • –GnRH-dependent – early activation of HP axis
  • ——-nc. LH using ultrasensitive immunoassay

GnRH-independent:

  • Usually CAH
  • Tumors of adrenals or ovaries
  • Steroid measurement, imaging

Primary amenorrhea

  • –No menses by age 16
  • –Turner’s syndrome (45,X(O) karotype)
  • –Pure gonadal agenesis
  • –Mullerian duct agenesis/dysgenesis
  • -Absent uterus or vagina
  • –Androgen insensitivity (testicular feminization)
  • –Congenital adrenal hyperplasia
  • —Hypothalamic or pituitary

Elevated FSH indicates ovarian non-response
Chromosomal testing indicated
Low FSH/LH suggest 2° or 3° issue

17
Q

What is Andogen Insensitivity Syndrome

A
X-linked defect of androgen receptor
Lack of androgen cellular effects
Wolffian development fails
---Testosterone ineffective
Mullerian development “normal”
--Anti-mullerian factor present
-------Blocks upper genital tract development
Genotypic XY, phenotypic female
Intra-abdominal testes
Normal to high testosterone, high LH
18
Q

Describe secondary amenorrhea.

A

Secondary amenorrhea
Loss of normal menses for ≥6 months
Pregnancy
Polycystic ovary syndrome (PCOS)
Ovarian tumors, premature ovarian failure
Late-onset CAH, Cushing’s syndrome, adrenal tumors
Pituitary disorders, incl. hyperprolactinemia
Hypothalamic, excessive exercise, stress
Drugs

History very important
Lab testing similar to primary amenorrhea except no genetic testing

19
Q

What is PCOS?

A

Polycystic Ovary Syndrome (PCOS)

May comprise 80-90% of anovulatory infertility
Prevalence up to 20%
More common in Hispanic and South Asian women
Less common in women of Chinese or Japanese descent
Diagnosis requires two of the following:
Presence of hyperandrogenism and/or hyperandrogenemia
Irregular or absent ovulation
Presence of polycystic ovaries by ultrasound

20
Q

Describe Hyperandrogenism in PCOS

A

Hyperandrogenism:
Hirsutism – male hair pattern (beard, trunk)
Virilization – inc. muscle mass, deepening voice
More common in androgen-secreting tumors

21
Q

Describe Hyperandrogenemia in PCOS

A
Hyperandrogenemia:
ASD, DHEA and/or testosterone increased
DHEA-S normal; elevated indicates adrenal origin
50% are obese, many have acne
Insulin resistance
LH elevated, FSH normal to low
LH:FSH >2.5 suggestive (with symptoms)
22
Q

Describe the male HPG Axis

A
GnRH stimulates FSH and LH release
FSH – Sertoli cells
-Spermatogenesis
-Inhibin secretion (dont worry about it) (↓ FSH)
LH – Leydig cells
-Synthesize testosterone
Testosterone
-2° sexual characteristics
-Anabolic actions
-Spermatogenesis
23
Q

What are the male steroids? (Androgens)

A
Testosterone (T)
-Secondary sexual characteristics
-Inc. muscle and bone mass (anabolic)
-Libido 
-Promotes spermatogenesis
Dihydrotestosterone (DHT)
-5α-reductase in prostate and skin
-Biologically active form of testosterone
---Similar to T3
---Rarely measured
Dehydroepiandrosterone (DHEA)
Androstanedione (ASD)
----Both are precursors to T and DHT
24
Q

Testosterone (bound vs free)

A

Bound to plasma proteins
Sex-hormone binding globulin (SHBG) – ~60%
Low capacity, high affinity
Estradiol also bound
Albumin – high capacity, low affinity - ~35%
Free – 2-3%
Controversy as to whether only free (2-3%) or weakly bound (37-38%) are biologically active

25
Q

How is Testosterone measured?

A

Competitive immunoassay
Suitable for adult males (ref. int. 260-1000 ng/dL)
Direct immunoassay not recommended for females or prepubertal males
Cross-reactivity with other steroids
Req. extraction and chromatography before immunoassay
LC-MS/MS preferred

LC-MS/MS
Requires enhanced sensitivity instrument (>$300K)

26
Q

Free vs Bioavailable Testosterone?

A

Free testosterone
Equilibrium or direct dialysis (cf free T4)
Mass action calculation
Measured testosterone
Measured SHBG (sandwich immunoassay)
Measured or assumed (4.3 gm/dL) albumin
Known binding constants: Testo:SHBG and Testo:Alb

Bioavailable testosterone
As for free except albumin-bound and free testo are both considered to be bioavailable

27
Q

Is the 17-Ketosteroids (Urine) test still used?

A

Obsolete test for androgens
Performed on 24 hr urine
Chemical summation of all by Zimmerman reaction
Many drug interferences, positive and negative
Occasionally fractionated by chromatography
Serum DHEA-S preferred

28
Q

Disorders of male reproduction.

A

Hypogonadotropic hypogonadism

  • Panhypopituitarism (2°)
  • Hypothalamic syndromes (3°)
  • GnRH deficiency (3°)
  • Hyperprolactinemia (suppresses GnRH, 3°)
  • Malnutrition, anorexia
  • Characterized by decreased testosterone (120 mIU/mL)
29
Q

What is hCG

A

Human Chorionic Gonadotropin

Heterodimeric protein (α- same as FSH, LH, TSH; ß)
Synthesized by syncytiotrophoblastic tissue (placenta)
-Also synthesized in pituitary (minimal)
Maintains corpus luteum function during pregnancy
As a laboratory test:
—Detect pregnancy
—Evaluate quality/viability of pregnancy
—Evaluate possible ectopic pregnancy
—Monitor choriocarcinoma and germ cell tumors

“Beta” hCG – an ambiguous term denoting specificity to hCG (w/o LH cross-reactivity)
Superfluous with current assays

30
Q

Describe hCG Metabolism

A

Intact – α:ß native heterodimer
Nicked – cleaved bonds in ß-chain
—May affect Ab recognition
Free subunits – some assays detect only intact
ß-core fragment – primary urinary form
—-Serum assays must be validated to detect hCG in urine

31
Q

Two types of pregnancy tests

A
Serum tests:
-Cutoff 25 mIU/mL
-Detection 3-5 days before missed period
Urine tests
-Cutoff 20-25 mIU/mL
-Detection period highly variable
Depends on urine specific gravity (~osmolality)
---Dilute urine = lower sensitivit
32
Q

What is ectopic pregnancy?

A

A pregnancy with an abnormal implantation site
May spontaneously abort or rupture
Ruptured ectopics are medical emergencies

hCG discriminatory zone –
hCG >1000-1500 mIU/mL - should be able to see intra-uterine pregnancy by transvaginal ultrasound
hCG

33
Q

What can produce non-placental hCG?

A
Tumors
Pituitary – increases with age
Peri-menopausal woman (41-55 yrs) 
Reference interval: 5.0-14.0 mIU/mL
FSH >20 mIU/mL makes pregnancy unlikely 
Clin Chem 51(10):1830-35(2005)