Gonadal Physiology

Front 1

Diagram of gonadal development:

Back 1

Front 2

3 critical transcription factors in gonadal development:

Back 2

SF-1 (steroidogenic factor 1) helps gonad and adrenal to form normally.

WT1 (Wilms tumor protein): helps gonad and kidney to form normally.

SRY: On Y chromosome aka testis determining factor--without it, a testis won't form.

Front 3

Sex determination is regulated by several critical genes...what are they?

Back 3

*SRY- testis determining factor on Y; mutations common (15-20%) in XY females; functions as DNA binding protein to:
-Induce Sertoli cell differentiation
-Formation of genital ridge
-Develop male-specific vasculature in gonad

*WT1- Wilms tumor gene 1; transcription factor critical for urogenital development

*SF-1-Steroidogenic factor 1; critical transcription factor for adrenal and gonads; regulates urogenital development, Anti-Mullerian Hormone (AMH)

Front 4

Charts of gonadal development during fetal life in first trimester:

Back 4

*Sexual Differentiation: chromosomes-->gonads-->T/E2
*AMH determines whether or not you have a uterus...mutations can occur here giving males pieces of uterus.

Front 5

Genital Differentiation:

Back 5

*8 weeks:“bipotential” genital tubercle

*8-12 weeks: internal duct development, AMH; androgens virilize external genitalia

*12-14 weeks: androgens fuse urethral folds, corpus; testes begin transabdominal descent

Front 6

Back 6

8 weeks: Bipotential gonad
L: male
R: female
*Can't tell a difference at 8 weeks

Front 7

Back 7

9 weeks: Critical Period of Virilization
L: male
R: female
*raphe has started closing on male
*stuff can go wrong at this stage in development

Front 8

Back 8

Differentiation complete by ~13 weeks
L: male @ 10 weeks
R: female @ 13 weeks
*raphe nearly closed on male
*female w/ labia, clitoris, urethra, vagina

Front 9

Disorders of Sex Development:

Back 9

*Ambiguous genitalia: external genitals are not obviously male or female

*DSD: condition of atypical sexual development

*Gender assignment: “boy” or “girl” historically assigned by medical staff.

*Gender identity: a person’s perception of their gender: male, female (or in-between?)

*Gender orientation: the gender to which you are sexually attracted, or your choice of partner

*Sexuality: a person’s erotic desires, sexual practices, sexual orientation

Front 10

Ambiguous Genitalia: Rules of Evaluation--

Back 10

1. Testes descend, ovaries do not.
Bilateral gonads papable: undervirilized male
Unilateral gonad palpable: undervirilized male
No gonads palpable: R/O virilized female

2. Degree of virilization reflects androgen exposure.

3. Presence of uterus indicates no testicular AMH.
Normal uterus: likely female
Hemiuterus: gonadal dysfunction

Front 11

Hypotalamic-Pituitary cascade leading to puberty:

Back 11

Front 12

Kiss-1:

Back 12

*Activation of pulsatile GnRH secretion by hypothalamic neurons initiates puberty

*Kisspeptin activation of its G-protein coupled receptor GPR54, expressed on GnRH-secreting neurons, stimulates synthesis/release of LH, FSH

*Kisspeptin increases at puberty, appears to be regulated by LEPTIN, and continues to regulate GnRH

*GPR54 loss of function point mutations/deletions cause familial or sporadic DELAYED puberty; gain of function mutation causes PRECOCIOUS puberty

Front 13

Mechanism of KISS-1 action:

Back 13

1.After birth, FSH>LH increases and declines by age 2 years --> central inhibition of GnRH by neurotransmitters

2. Just before puberty: GABA inhibition decreases as Kisspeptin increases.

3. Peripheral signals leptin and IGF-I promote GnRH secretion; pulsatile GnRH stimulates FSH then LH.

Front 14

Puberty in girls:

Back 14

Front 15

Timeline of Normal Female Puberty:

Back 15

thelarche=onset of breast development

Front 16

Menstrual/ovulation cycle:

Back 16

1.Ovary is full of primordial follicles (2 X 10^6 at birth declines to ~4 X 105 at puberty and continues to decline)

2.In late childhood, GnRH becomes pulsatile to increase FSH then LH; LH becomes pulsatile at night

3. Follicles contain oocyte, granulosa and theca cells; FSH and LH stimulate growth of follicles, E2 production (granulosa and theca cells) and more follicular growth

4.Ovarian E2 production promotes breast and uterine growth, bone maturation, liver protein synthesis

5. LH surge midcycle triggers ovulation; PG produced by corpus luteum rises then falls to induce bleeding

6. Menarche: first withdrawal bleed from episodic E2

Front 17

Follicular Phase of menstrual cycle:

Back 17

FSH
-stimulates growth of 8-12 follicles, theca cells
-stimulates granulosa cells to produce E2 and INHIBIN B, which restrain FSH as E2 rises, allowing dominant follicle to mature

LH
-stimulates theca cells to produce androgens (for E2 synthesis)
-stimulates granulosa cells in late follicular phase to produce progesterone (PG)

Ovulation
-Prior to ovulation, dominant follicle emerges: its E2 production inhibits FSH
-E2 rise feedbacks POSITIVELY to increase LH and small increase in FSH, resulting in large LH surge, PG production
-Follicle swells, ruptures and discharges the ovum 16-20 hours after LH surge

Front 18

Luteal Phase of menstrual cycle:

Back 18

1. Collapsed follicle forms corpus luteum
2. Corpus luteum makes Inhibin A, PG and E2
3. Without fertilization, corpus luteum involutes, E2 and PG production declines, and withdrawal bleeding occurs

*PG levels are a good sign of ovulation*
*Decline in PG/E2 makes withdrawal bleed happen*

Front 19

Graphic of hormone levels during menstrual cycle:

Back 19

Front 20

Endometrial Cycle: 3 Phases in Uterus

Back 20

E2 promotes cell proliferation, glandular and vascular growth -->post-ovulation, secretion of mucus, nutrients in preparation of fertilized egg --> loss of PG and E2 leads to necrosis of cells and vessels, desquamation and menses

Front 21

Menopause:

Back 21

*Permanent end of menstruation and fertility, defined as occurring 12 months after a woman’s last menstrual period.

*Triggered by the number of ovarian follicles falling below a threshold number.

*Follicle numbers decline bi-exponentially with age to ~1000 (2 million at birth!) at ∼51 years, indicating the menopausal threshold because it corresponds to the median age of menopause.

*With follicle loss, estrogen and INHIBIN decline, FSH increases first then LH due to lack of feedback.

Front 22

Pubertal development in boys:

Back 22

*GnRH stimulates LH and FSH secretion

*LH acts on Leydig cells, which make Testosterone (and E2); major negative regulators at pituitary and hypothalamus

*FSH acts on Sertoli cells: Inhibin B is major negative regulator at pituitary; Activin stimulates FSH

*Spermatogenesis requires FSH, Testosterone

Front 23

How does puberty in boys begin?

Back 23

*Begins when FSH acts on Sertoli cells: Seminiferous tubules (composed of sertoli cells and germinal cells) begin to grow and the testes enlarge >2.5 cm length (>4 cc volume)--these numbers define start of puberty.

*LH acts on Leydig cells: Testosterone is synthesized, secreted and virilization begins

*Spermatogenesis begins in mid-puberty and requires FSH and local testosterone (delivered from Leydig cells by ABP)

*Peak growth velocity occurs in late puberty

Front 24

Normal Male Puberty age timeline:

Back 24

-Testes enlarge
-Virilization begins
-Growth spurt

Front 25

Describe the 2 cell types involved in testes development:

Back 25

*Sertoli cells:
-fetus: produce Anti-mullerian hormone (AMH) to inhibit Mullerian structure development
-puberty: proliferate, surround spermatogonia in tubules, make androgen binding protein (ABP) & Inhibin B

*Leydig cells:
-fetus: located in the testis interstitium; make Testosterone which controls wolffian duct development; DHT controls external genitalia development
-puberty: Testosterone increases and is converted to DHT which controls virilization; spermatogenesis begins

Front 26

Testosterone Metabolism:

Back 26

*Testosterone converted in peripheral tissues to DHT or estrogen.

*DHT promotes virilization; estrogen closes epiphyses.

*Estrogen promotes breast development in ~50% of pubertal boys (pubertal gynecomastia).

Front 27

Testosterone Transport, Mechanism of Action:

Back 27

Transport:
*60% T/DHT/E2 binds SHBG (affinity T> E2)
*T/E2 change [SHBG] to affect hormone action by changing free T: SHBG decreases at puberty in boys, increases in girls
*38% T/DHT/E2 binds albumin with lower affinity (brain uptake)

Androgen receptor:
*X chromosome
*Higher affinity for DHT than T; may affect transcription
*AR expression high in reproductive organs>skin> muscle
*Unbound in the nucleus, binds DNA with ligand

Front 28

Regulation of spermatogenesis diagram:

Back 28

*ABP presents DHT to the germ cell for spermatogenesis.

Front 29

Testosterone decline with age chart:

Back 29

*Spermatozoa and ejaculate volume decrease more slowly with age

Front 30

Hypogonadism: discuss 1˚ and 2˚ causes-

Back 30

*Primary aka HYPERgonadotrophic: ovary/testes failure
*it can be:
-acquired (e.g., drugs, irradiation, autoimmune)
-genetic (e.g., Turners, Klinefelters, dysgenesis)
-Menopause: “run out” of follicles: ovulation and E2 synthesis decrease
*LH/FSH will be elevated b/c there's no feedback*

*Secondary or hypogonadotrophic aka central:
-Congenital (e.g., MPHD)
-Genetic (e.g., Kallman’s, Prader-Willi)
-Acquired (e.g., anorexia, chronic disease, weight loss, tumors, prolactinoma, morbid obesity)
*LH/FSH will be low in anorexia...there's no GnRH stimulation to pituitary, so no LH/FSH secretion.

Front 31

Neuroendocrinology of Sexual Function: Libido--

Back 31

*LIBIDO-i.e. desire: depends on testosterone in both sexes; dopamine (and E2) promotes and prolactin inhibits libido.

*Parasympathetic NS- AROUSAL in the form of sexual sensations stimulates PNS (NO, Ach) to increase blood flow to erectile tissue (penis and clitoris; swelling of labia) and increase vaginal secretions.

*Sympathetic NS- intense sexual stimuli cause reflex centers of spinal cord to activate SNS (NE) and initiate ORGASM (emission and ejaculation in males, emission and contraction in females); Serotonin is inhibitory.

*PRL levels increase after orgasm for ~60 minutes...more in men...hence "recovery period."

*Interruption by psychic factors (arousal) or drugs (esp that ↑ 5-HT or DA) can affect sexual functioning.

Front 32

GRAPHICS of desire, arousal, and orgasm:

Back 32

Front 33

how does viagra work?

why doesn't it work for women?

Back 33

*Inhibits a phosphodiesterase --> increase in cGMP --> increase in NO --> vasodilation --> erection

*Men can jump back and forth b/t arousal and desire. For women, it's linear; must have LIBIDO before arousal. So if a man has an erection, that can lead to libido. Doesn't work that way for females.

Front 34

important hormones in orgasm:

Back 34

-5-HT and NE

Front 35

How would you treat low libido in women?

Back 35

-Low dose testosterone.