The Detergents And Disinfectants For Instruments And Surfaces (Hexanios - Surfanios)

Gonadotropin Releasing Hormone (GNRH - LHRH)

• GnRH is synthesized from the hypothalamic arcuate nucleus  and is a pulsatilely released decapeptide.

• GnRH-secreting neuronal cells originate from the olfactory area and migrate to the arcuate nucleus in embryogenesis by means of cranial nerves. As a result of the lack of migration from this olfactory region, genetically GnRH deficiency occurs, this situation is called Kallmann Syndrome.

• The half-life of GnRH is 2-4 minutes.

• GnRH stimulates the synthesis, secretion and storage of FSH and LH from the anterior pituitary.

• GnRH pulses are high-frequency and low-amplitude in the follicular phase, and low-frequency and high-amplitude in the luteal phase.

Control of GNRH Release

• The pulsatility of GnRH is directly affected by the dual catecholaminergic system: Norepinephrine activator is dopamine inhibitor. This system is basically under the influence of endogenous opiates, Increased opiate tone in the clinic appears as hypothalamic amenorrhea, Endogenous opiates inhibit gonadotropin release by suppressing GnRH release from hypothalamus, Endorphin level changes significantly during menstrual cycle, highest in the luteal phase , least during menstruation.

• Sex steroids suppress GnRH by increasing central endorphin release.

Control of GnRH release

Inhibitors of GnRH release

 Dopamine

 Gonadotropins (negative feedback)

 Endogenous opiates

 Estradiol (increases opiate production) Progesterone (increases opiate production)

 CRH (increases opiate production)

 Melatonin

 Serotonin

 GABA

Those that stimulate the release of GnRH

 Norepinephrine (noradrenergine)

 Neuropeptide Y

 Acetylcholine

 VIP

 Naloxone

 Kispeptin

GNRH Analogs

• GnRH Agonists: Leuprolide, goserelin, nafarelin, buserelin etc.

- While increasing FSH and LH secretion with endogenous GnRH-like effect following pulsatile administration of GnRH agonists; As a result of continuous infusion, first a short-term increase in FSH and LH secretion (exacerbation, flare-up) with a GnRH-like effect, followed by receptor down-regulation within 2 weeks, gonadotropin secretion is inhibited (medical oophorectomy).

• GnRH Antagonists: Cetrorelix, ganirelix.

- Antagonists compete with natural GnRH competitively, bind to GnRH receptors and rapidly suppress gonadotropins within 24-72 hours. In addition, the flare-up effect observed initially in agonists does not occur.

• Indications of GnRH Analogs

- Endometriosis

- Hormone-dependent tumors (endometrial cancer, breast cancer, etc.)

- Myoma uteri

- Central (true) or idiopathic precocious puberty IDU (Dysfunctional uterine bleeding)

- Ovarian hyperandrogenism

- Premenstrual syndrome

- Ovulation induction

• Side Effects of GnRH Analogs

- Hypooestrogenemic environment, hot flushes, vaginal dryness, irregular bleeding, headache, depression, decreased emotional lability and libido, trabecular bone loss, reduction in breast size, arthralgia, myalgia, insomnia, edema

- The most important side effect is osteoporosis, which occurs in use for 6 months or more. Doesn't exactly come back. Low-dose estrogen is added to long-term GnRH analogue therapy programs to prevent osteoporosis (replacement therapy).

Gonadotropins (FSH And LH)

Gonadotropins are glycoprotein hormones released from basophilic cells in the adenohypophysis. A subunits of all glycoprotein hormones (FSH, LH, TSH and hCG) are common. It is the B subunit that makes the difference.

- However, the B subunit of hCG and LH shows 96% similarity. At the same time, LH and hCG act by binding to the same receptor.

- Gonadotropins are metabolized in the liver and kidneys and most of them are excreted in the urine. The half-life of LH is 20 minutes, while the half-life of FSH is about 3-4 hours, and that of ᵝ-hCG is 24-36 hours.

FSH (Follicle Stimulating Hormone)

• Its receptors are on granulosa cells .

• Effects of FSH:

- Granulosa cell proliferation and estrogen production in the follicles

- FSH and LH receptor formation in granulosa cells

- Aromatase and 3ß-hydroxysteroid dehydrogenase enzyme activation

- Stimulation of follicles and protection from apoptosis

While there is no LH receptor in the granulosa cells at the beginning of follicular development, when the preovulatory follicle stage is reached (on the 11th-12th day of the cycle), LH receptors begin to form on the granulosa cells with FSH stimulation.

LH (Luteinizing Hormone)

• Its receptors are mainly found on theca interna cells.

• Effects of LH:

- Theca interna cell proliferation and androgen production

- Luteinization and progesterone production when the LH receptor appears in the granulosa cells (days 11-12 of the cycle)

- Ensuring ovulation

- Completion of I. meiosis in oogenesis (conversion of primary oocyte to secondary oocyte)

Ovarian Peptides

inhibin

- Released from granulosa, Sertoli, placenta and small amounts from pituitary basophilic cells

- has two forms; inhibin-A and inhibin-B. Inhibin selectively inhibits the release of FSH.

- Inhibin-B inhibits FSH in the follicular phase and inhibin-A inhibits FSH in the luteal phase.

- Inhibin stimulates LH a activity locally, stimulates IGF release from both granulosa and theca interna cells and increases androgen production.

- The levels of inhibin-B at the beginning of the follicular phase (first 4 days of the cycle) are used as an indicator of ovarian reserve.

- inhibin-A is also used as a marker in Down syndrome (inhibin-A increases in Down syndrome).

activin

- Released from granulosa cells and to a lesser extent from pituitary basophilic cells

- Activin selectively activates the release of FSH. Activin also locally suppresses LH activity and suppresses both androgen production from theca interna cell and progesterone production from luteinized granulosa cell.

follistatin

- Released from granulosa cells and pituitary basophilic cells.

- Follistatin inhibits FSH release indirectly by binding activin (also known as FSH-suppressive protein).

- Inhibin, activin and folistatin; It belongs to the transforming growth factor-B family.

Ovarian Growth Factors

Insulin-Like Growth Factors (IGF I-II)

They have a growth hormone-like effect. IGFs are released from theca, granulosa and lutein granulosa cells.

- Stimulates steroidogenesis in both granulosa and theca cells.

Effects of IGF

- Stimulates androgen by increasing the effect of IGF LH on theca (basic effect)

- Provides the formation of FSH and LH receptors in granulosa cells

- Causes proliferation of granulosa cells

- Increases aromatase activity. Increases progesterone synthesis.

Epidermal Growth Factor (EGF)

- The intraovarian growth factor that inhibits FSH is EGF.

Ovarian Steroid Hormones

- All steroid hormones are synthesized from cholesterol. Transmission of cholesterol between tissues is via lipoproteins (LDL).

- The ovary produces all 3 sex steroids; however, it differs from the adrenal gland in the absence of 21-hydroxylase, 18-hydroxylase reductase, and 11ß-hydroxylase. Therefore, glucocorticoids and mineralocorticoids cannot be produced in the ovary.

- Steroidogenesis proceeds with the loss of carbon.

steroidogenesis

Enzymes	Location	Reactions
P450scc P450c11 P450c17 P450c21 P450arom (cyp19)	mitochondria mitochondria endoplasmic reticulum endoplasmic reticulum endoplasmic reticulum	cholesterol side branch separator 11-hydroxylase. 18-hydroxylase. 19 methyloxidase 17-hydroxylase 17,20-lyase 21-hydroxylase aromatase

- Steroidogenetic enzymes are cytochrome P450 oxidase group enzymes. 17ß hydroxysteroid dehydrogenase and 5a-reductase reactions occur with non-P450 enzymes.

Steroid Hormones

Steroid hormones circulate in the circulation either bound to plasma proteins or free. The biologically active form of the hormone is the free form.

- Most of estradiol and testosterone are carried in the blood by sex hormone binding globulin (SHBG), which is a β-globulin and is synthesized in the liver.

Transport of Steroids
	Free	Albumin	SHBG	Transcortin
Estrogen	1%	30%	69%	-
testosterone	%1-2	%20-32	%66-78	-
DHEA	4%	88%	8%	-
androstenedione	7%	85%	8%	-
progesterone	2%	80%	%<1	18%
cortisol	10%	15%	-	75%

- Progesterone is mainly transported in the circulation by albumin. 

- Sex steroid with the least binding to SHBG: Progesterone 

- The only sex steroid that can be transported by transcortin: Progesterone 

- Sex steroid with the highest free form: Androstenedione

- SHBG levels may vary depending on various factors. Accordingly, free bioactive hormone levels also differ.

Control of SHBG Release

Those that increase the release of SHBG

• Hyperthyroidism and thyroid hormones

• Estrogen

• Combined oral contraceptives

• Pregnancy

• Luteal phase

• Tamoxifen

• Rosiglitazone (thiazolidinedione)

• Cirrhosis

Those that reduce the release of SHBG

• Hypothyroidism

• Steroids

• With progestin

• Androgens and hyperandrogenism

• Acromegaly and GH

• Hyperprolactinemia

• Hyperinsulinemia (insulin resistance) and IGF

• Obesity

Estrogens

- C-18 (18 carbons) steroids:

• Estrone (E1): It is a relatively weak estrogen. Although it is produced in the ovary, it is peripheral estrogen as the theme.

• Estradiol (E2): It is the most potent and most produced estrogen in the reproductive period.

• Estriol (E3): It is the weakest estrogen, metabolic end product, not secreted from the ovary.

• Estertrol (E4): It is formed in the fetal liver, is maximum at term, its activity decreases in infancy and cannot be detected in adults and has no clinical use.

Predominant estrogen in the reproductive period; estradiol (E2) 

Predominant estrogen in prepubertal and postmenopausal periods; estrone (E1)

 Estrogens are obtained by aromatization of androstenedione and testosterone in the ovary and by aromatization of androstenedione in the periphery. In the follicular development process, androstenedione and testosterone are produced in the theca cells of the follicle under the influence of LH. These androgens produced in theca cells pass into the granulosa cells by passive diffusion, where they are aromatized by the effect of FSH. Estrone (E1) from androstenedione and estradiol (E2) from testosterone are obtained (aromatization) (two cells - two gonadotropin theory).

 Estrogens are metabolized in the liver and excreted in the bile. Estriol is a peripheral metabolite of estradiol and estrone and is not released from the ovary.

Effects

Urogenital System

- Increases proliferation in urethral epithelium.

- Increases proliferation and superficial cell dominance in the vaginal epithelium.

- It decreases vaginal pH by increasing glycogen storage in vaginal stratified squamous epithelium (pH 3.8-4.5).

- Increases the liquid Content of cervical mucus, reduces its viscosity (hypoviscous) and increases its elasticity (Spinnbarkeit).

- It causes a fern appearance by increasing sodium chloride (NaCl) crystallization in cervical mucus (Ferning).

- Increases the pH of cervical mucus and makes it alkaline.

- It makes proliferation in the gland and stroma of the endometrium.

- Increases the formation of progesterone receptors in the endometrium.

- Increases uterine contractility by increasing uterine smooth muscle cells, gap junctions, contractile proteins (connexin 43) and myometrium's sensitivity to oxytocin.

- Increases ciliary activity and motility in the tuba.

- Stimulates follicular development in the ovary.

Breast

- Provides ductal development.

Secondary sex characters

- It is effective in breast development at puberty (thelarche).

Bone

- Increases bone density by increasing osteoblastic activity in bones.

Skin

- Increase vascularity and collagen content

Liver

- Increases SHBG synthesis.

- Corticotropin-binding globulin (transcortin) increases the synthesis of thyroxine-binding globulin.

- Increases angiotensinogen.

- Increases coagulation factor production (F II, VII, VIII, IX, and X)

- Decreases the production of antithrombin.

- Increases triglycerides.

- Increases total cholesterol and HDL, decreases LDL.

- By increasing the bile salt concentration, it facilitates the formation of gallstones (cholesterol stones).

Feed-back effects

- Gives negative feedback on FSH.

- Makes positive feedback on LH (before ovulation).

- Suppresses GnRH (by increasing central opiad tone).

Other

- Causes water and salt retention.

estrogen antagonists

- Pure antiestrogen: Fulvestrant

- Mixed antiestrogens (SERM) (clomiphene, tamoxifen, droloxifen, toremifene raloxifene):

 Clomiphene: It is a partial agonist. It has agonistic effects at the hypothalamic and pituitary levels. It remains attached to the estrogen receptors there for a long time. As a result, the hypothalamus cannot detect the amount of estrogen in the circulation and increases the release of GnRH and FSH. With this effect, it is used in ovulation induction. Ovulation rates with clomiphene are high, but pregnancy rates are low due to its antiestrogenic effect in the uterus, cervix and vagina.

 Tamoxifen: It is a competitive inhibitor of estrogen at the receptor level. It is antiestrogenic in breast tissue and estrogenic in endometrium. It can stimulate the development of endometrial polyp (most common endometrial side effect), endometrial hyperplasia and endometrial cancer; may exacerbate endometriosis. Tamoxifen decreases antithrombin and LDL while increasing HDL and SHBG. Protects bones, is estrogenic on the vaginal mucosa.

 Raloxifene: Antiestrogenic in uterus and breast, estrogenic effect on bone and lipids (does not affect HDL).

 Ospemifene: It is used in the treatment of genitourinary symptoms such as vaginal atrophy and dyspareunia in postmenopausal women.

 Bazedoxifene: It is used in the prophylaxis of postmenopausal osteoporosis by being combined with estrogen.

progesterones

 Progesterone is a C21 steroid hormone secreted largely from the corpus luteum and placenta. Smaller amounts are also released from the adrenal cortex.

 Progesterone is metabolized in the liver and excreted in the urine.

Effects

Urogenital System

- Increases vaginal pH by decreasing glycogen storage in vaginal stratified squamous epithelium (pH > 4.5).

- Increases intermediate cell dominance in the vaginal epithelium.

- It reduces the liquid content of cervical mucus, increases its viscosity (hyperviscous), forms a mucus plug and reduces its elasticity.

- Decreases the pH of cervical mucus and makes it acidic.

- It has antimitotic and antiproliferative effects on the gland and stroma of the endometrium.

- It prepares the endometrium for nidation by causing secretory changes in the endometrium proliferating with estrogen.

- It has antiestrogenic effect on the endometrium.

• Decreases estrogen receptor formation in the endometrium

• Increases the conversion of estradiol (E2) to estrone (E1) (by stimulating the 17ß OHSD enzyme).

- It causes relaxation in the uterus by reducing the smooth muscle cells, gap junctions, contractile proteins (connexin 43) of the uterus and the sensitivity of the myometrium to oxytocin.

- It decreases ciliary activity and motility in the tuba.

Breast

- Provides the development of lobules and alveoli.

Bone

- Increases bone density with antiresorptive effect on bones.

Liver

- Decreases SHBG synthesis.

Feed-back effects

- It gives negative feedback on LH.

- Gives positive feedback on FSH (before ovulation).

- Suppresses GnRH (by increasing central oplad tone).

Other

- It is thermogenic, increases body temperature.

- Causes water and salt retention.

- Provides natriuresis by blocking the effect of aldosterone at high doses.

Progesterone Antagonists:

- Mifepristone, ulipristal, and onapristone are selective progesterone receptor modulators (SPRM). In addition to the antagonistic effect of mifepristone, it also has a mild progestagenic effect in the absence of progesterone in the environment.

- Epostan is an agent that inhibits the production of progesterone.

Androgens

Androgens originate from the adrenal gland, ovary, and peripheral. Androgen production is under the control of LH in the ovary and ACTH in the adrenal gland.

• Adrenal androgen production

- With the stimulation of the adrenal gland with ACTH, androgen production occurs in the zona reticularie and zona fasciculata regions of the adrenal cortex.

- The main androgen produced in the adrenal gland is DHEA-S and is used in the evaluation of adrenal pathologies. However, large amounts of DHEA, androstenedione and testosterone are also produced.

• Ovarian androgen production

- The major androgen products of the ovary are androstenedione, testosterone and DHEA. They are secreted from theca interna cells.

• Peripheral androgen production

- The majority of circulating testosterone in women is obtained by peripheral conversion from androstenedione .

- DHT is the most potent androgen. It is obtained almost entirely by the reduction of testosterone and androstenedione in target tissues by 5a reductase.

There are two 5a-reductase isoenzymes.

  Type 1 is most abundant in the skin, and type 2 is most abundant in the liver, prostate, seminal vesicle, and genital skin.

  The affinity for type 2 is 20 times higher than type 1 for testosterone

DHT is not found in circulation.

Androgens
Androgens	potency	ovary	Adrenal	Peripheral
DHEA	-	25%	50%	25%
DHEA-S	5	-	100%	-
androstenedione	10	50%	50%	-
testosterone	100	25%	25%	50%
DHT	300	-	-	100%

Metabolism of Androgens

- All androgens are excreted in the urine as 17 ketosteroids. DHT is inactivated by reduction to 3a-androstanediol glucuronide, and 3a-androstanediol glucuronide can be used as a marker of peripheral androgen metabolism.