Biosintesis Hormon Reproduksi

Hypothalamus/Pituitary/Reproductive Organ Axis

Mekanisme Kerja Hormon Steroid

Mekanisme…

• Steroid hormones penetrate the plasma membrane and bind to intracellular receptors in the nucleus or cytoplasm.

• Hormone binding activates the receptor, hormone response elements, HRE on DNA to initiate transcription and formation of the proteins that express the hormonal response.

Reseptor Steroid

• Membrane receptors that interact with kinases. – estradiol (E2) binds to an intracellular receptor protein

(ER) that dimerizes and translocates to the nucleus– Estradiol also affects ion channels and G-protein-

coupled receptors, independent of the ER nuclear transcription factors

– receptor complex, made of the receptor protein and coactivators, binds to the palindromic sequences (GCTAATCG) that constitute the estrogen response element (ERE) and affect gene transcription

Steroid

Cholesterol

Steroid

• Cortex Adrenal : Steroid– Cortisol– Androgen

• Laki-laki: Testosteron• Wanita : Estrogen dan progesteron

Male

Testis

• Sel Leydig :androstenediol, androstenedione, testosterone, dihydrotestosterone, dan dehydroepiandrosterone (DHEA)

• Sel Sertoli: merubah testosterone menjadi estrogen (<); estradiol(E2) (spermatogenesis).

• FSH dan LH: proliferation Leydig cells• LH upregulates 3β-hydroxysteroid

dehydrogenase, (last step in testosterone formation)

Testis

Testis….

• Testicular androgens : mostly produced by the Leydig cells under the influence of pituitary luteinizing hormone (LH).

• Sertoli cells: sperm proliferation and maturation and convert androgens to– estrogens via aromatase – Dihydrotestosterone via 5α-reductase– secrete inhibin to regulate LH release

FSH- LH

• FSH & LH: glycoprotein hormones,synthesized and secreted by a single class of pituitary cells

• LH: Leydig cells– Receptors: heterotrimeric G-proteins (cyclic AMP )– activates protein kinase A, promote

steroidogenesis, gene transcription, and other cellular functions

• FSH : Sertoli cells in the germinal epithelium

Actions of FSH and LH on the testis.

Regulation, hormonal products, and interactions between Leydig and Sertoli cells

Biosintesis Testosteron & Progesteron

Dihydrotestosterone (DHT)

Intracellular mechanism by which LH stimulates testosterone synthesis.

Aromatase

• Adipose tissue is an important source of the enzyme aromatase that converts androgens to estrogen.

Metabolisme testosteron

Female

Biosintesis estrogen

Biosintesis estrogen• three hydroxylation steps,

each of which requires O2 and NADPH.

• The aromatase enzyme complex : P450 monooxygenase

Hormonal and ovarian events during the menstrual cycle.

Biosintesis Female Hormone

FSH & LH• Ovari: control the menstrual cycle. • FSH : ovarian granulosa cell proliferation and aromatase

activity to allow production of E2. • E2 increases, FSH stimulates increased LH responsiveness. • E2 and inhibin suppress FSH production at the level of the

hypothalamus and pituitary• release of a selected oocyte from th ovary (ovulation) and

transformation of granulosa cells into the secretory luteinized cells of the corpus luteum.

• Luteal cells make large amounts of P4, but also E2 and inhibin

FSH-LH …

• pregnancy does not occur : LH, sufficient to support the corpus luteum (for very long).

• P4, E2, and inhibin levels drop, FSH levels rise. Menstruation begins and the cycle repeats.

• pregnancy, luteal P4 supports the pregnancy until hormonal support is taken over by the placenta (typically 7–9 weeks of gestation).

• ovarian E2 and P4 directs the growth and differentiation of the uterine endometrium to prepare it for embryo implantation.

Prolactin & GH• Prolactin : controls the initiation of lactation. In contrast

to other pituitary hormones, it is not negatively regulated by classic feedback loops but rather by– local autocrine and paracrine factors– Neurotransmitters– peripherally produced steroid hormones. – Ovarian E2 and pituitary TRH are strong stimuli for prolactin

production.• Growth hormone (GH), insulin-like growth factors (IGFs),

IGF-binding proteins (IGFBPs), and IGF receptors of the somatotropic axis enhance ovarian steroidogenesis

Theca & granulosa cell cooperation in estrogen synthesis

LDL, low density lipoproteins; cAMP , cyclic adenosine monophosphate. PKA , protein kinase A; CREB , cyclic AMP response element binding protein; StAR , steroid acute regulatory protein; P450c17 , 17 α -hydroxylase/lyase; 17 β HSD , 17 β –hydroxysteroid dehydrogenase.

Theca & granulosa…..

• Theca cells produce androgens in response to LH .• Granulosa cells respond to FSH mainly by aromatizing

androgens to estrogens and to some extent by producing pregnenolone from cholesterol

• Granulosa cells : limited in their capacity to produce pregnenolone ;– little access to circ. cholesterol delivered by LDL– express few LDL receptors– minimal levels of P450scc needed to convert cholesterol

to pregnenolone

Theca & Granulosa cells• THECA

– direct capillary blood supply and express high levels of LDL receptors, and high levels of P450scc and P450c17.

– metabolize the 21 carbon pregnenolone to the 19 carbon androstenedione, but lack aromatase, and hence cannot synthesize estrogens.

• Granulosa • express ample aromatase, but cannot produce its 19

carbon substrate because they lack P450c17. • However, granulosa cells readily aromatize androgens

provided by diffusion from the theca interna.

Eff ects of Estrogen and Progesterone on the Reproductive Tract

Menopause• Cessation of ovarian follicular development with resultant

marked decreases in circulating estrogen, inhibin, and P4 levels. • Ovarian androgen production remains relatively intact. • Decreased estrogen and inhibin release, consequently FSH levels

rise. – hot fl ashes, insomnia, and depressed mood that are commonly found

in periand early postmenopausal women.– Estrogen deficiency: tissue atrophy and loss of elasticity in the breast,

vagina, and skin. • estrogen antagonizes the effects of parathyroid hormone on Ca

2+ mobilization in bone and since estrogen deficiency increases osteoclast activity, postmenopausal women are at increased risk for osteoporosis

Signaling of the Breast

• The suckling reflex: sensory impulses that travel from the nipple to the brain with breast-feeding

• Prolactin: aid in continued milk production. • Prolactin inhibits – secretion of FSH directly– indirectly through inhibition of the GnRH pulse

generator and appropriate pulsatile secretion of GnRH

OXYTOCIN•Oxytocin: uterus to contract and causes the cervix to stretch.

Oxytocin secreted in response to suckling.