Gonad Hormones : Female

1. Gonad Hormones : Female Prof.Dr.Gülden Burçak 2011-2012

2. Ovary : produces female sex hormones and female germ cells

3. The ovarian follicles are of two functional types; nongrowing ( primordial) and growing • Primordial follicles degenerate (atresia) • Mature ovarian follicle (graafian) consists three layers of cells : theca externa, theca interna and granulosa • The oocyte is contained within the follicular fluid • After rupture of the mature follicle and release of the ovum, granulosa and theca cells proliferate to form the corpus luteum. • Corpus luteum is a transient endocrine organ

4. Hypothalamic-Pituitary-Ovarian Axis • Constant pulsatile release of GnRH from the hypothalamus • Synthesis,storage and secretion of gonadotropins (FSH and LH) from the anterior pituitary • (-/+)Feedback relationships between the ovarian hormones (estradiol,progesterone) , GnRH, FSH and LH secretions • Cyclical ovarian function

7. (+) Feedback of gonadal steroids on pituitary • E2> 700 pmol/L,maintenance of elevated levels for at least 48 hours • Progesterone, only after the pituitary has been exposed to prolonged high levels of E2 • Chronic stress or profound weight loss can disrupt the pattern of GnRH secretion and lead to anovulation and amenorrhea.

8. In childhood : HPA remains highly sensitive to (-) feedback effects of gonadal steroids • In puberty : adrenarche, decreased sensitivity of HPA to (-) feedback and gonadarche, increased E2, onset of ovulatory cycles • androstenedione,DHEA, DHEAS: 6-8 years • pulsatile secretion of GnRH is critical in the initiation of puberty. • in girls FSH increases earlier than LH

9. Ovarian steroid hormones • Estrogens C18 (Granulosa) • 17 ß-Estradiol • Estrone : post-menopause • Estriol : inpregnancy • Progestagens C21 (Corpus Luteum) • Pregnenolone • Progesterone • 17 OH Progesterone • Androgens C19 (Theca) • DHEA, androstendione, testosterone, dihydrotestosterone

12. Aromatization of androgens in granulosa cells (also some estradiol in corpus luteum) • Three hydroxylation steps, O2 and NADPH • P450 mixed-function oxidase • Testosterone estradiol • Androstendione estrone • Peripheral aromatization of androgens • Adrenal androgens : DHEA (major but weak), androstendione (potent) • Conversion : 3β-hydroxy steroid dehydrogenase,Δ5,4 isomerase • During pregnancy and post-menopausal period • In adipose cells, liver, skin and other tissues • Increased aromatase activity , estrogenization in cirrhosis,hyperthyroidism, aging and obesity

13. Ovarian nonsteroidal hormones • Cytokines, growth factors and neuropeptides • Inhibins : multifunctional glycoproteins A and B • Inhibin A(αßA) is low in early follicular phase, high in the luteal phase ;inhibin B(αßB) parallels FSH • Inhibin B synthesized in granulosa cells and inhibin A in corpus luteum cells. • increase theca cell androgen production • Ovarian-pituitary negative feedback relationships • Activins : disulfide-linked dimers of the ß-subunits of inhibin. • Activin A produced in the ovary augments the effects of FSH • Activin B produced in the gonadotropes increases FSH secretion

14. 60% loosely bound to albumin (>3000mg/L) • 38% bound with high affinity to SHBG • % 2-3 is free • Progesterone binds strongly to CBG and weakly to albumin • The binding proteins provide a circulating reservoir of hormone • The metabolic clearance rates are inversely related to SHBG affinity • Conjugated derivatives are not bound

16. SHBG synthesis in hepatocytes • Increased by thyroid hormones, estrogens (5-10x),decreased levels of androgens,high carbohydrate diet, stress, aging, cirrhosis. • Decreased by androgens (2x) hyperprolactinemia, increased growth hormone, obesity, menopause, progestins, glucocorticoids. • The normal level of SHBG is about 30-50% lower in men than in women.

17. Metabolism of ovarian steroids • In the liver,estradiol (E2) and estrone(E1 ) are converted to estriol (E3) and conjugated with glucuronic a. or sulfate; excreted by the kidney • Oral estrogens are effectivebecause the activity of conjugating enzymes are low • Progesterone is converted to pregnanediol, conjugated (sodium pregnanediol-20 glucuronide) and excreted by the kidney • Some synthetic steroids have progestational activity and avoid hepatic metabolism;used as contraceptives

18. Estrogens • Maturation of primordial germ cells • Provision of the hormonal timing for ovulation • Developing the tissues that will allow for implantation of the blastocyt • Establishment of the milieu required for the maintenance of pregnancy • Provision of the hormonal influences for parturition and lactation • Anabolic effects on bone and cartilage • Vasodilation and heat dissipation

19. Progestins • generally require the previous or concurrent presence of estrogens • reduce the proliferative activity of the estrogens on the vaginal epithelium • convert the uterine epithelium from proliferative to secretory ; preparing it for implantation of the fertilized ovum. • enhance the development of the acinar portions of breast glands after estrogens have stimulated ductal development. • decrease peripheral blood flow, decrease heat loss

20. Menstrual cycle-Follicular phase • A particular follicle begins to enlarge under the influence of FSH • E2 and LH rise, E2 reaches its max. level 24 hours before the LH (FSH) peak and sensitizes the pituitary to GnRH • LH peak heralds the end of the follicular phase and precedes ovulation by 16-18 hours. • Follicle rupture ,releasing an ova • Continual administration of high doses of estrogen (oral contraceptives) supresses LH and FSH release and inhibits the action of GnRH on the pituitary

21. Menstrual cycle-Luteal phase • The granulosa cells of the ruptured follicle luteinize and form the corpus luteum • Corpus luteum produces progesterone and some E2 • Estradiol peaks about midway through the luteal phase and then declines to a very low level.The major hormone is progesterone • LH is required for the early maintenance of the corpus luteum and the pituitary supplies it for 10days. • If implantation occurs LH function is assumed by hCG • hCG stimulates progesterone synthesis by corpus luteum until placenta begins to make in large amounts • In the absence of implantation corpus luteum regresses causing a decrease in progesterone.

24. Placental hormones maintain pregnancy • Human chorionic gonadotropin hCG • structurally similar to LH • supports corpus luteum until placenta produces sufficient amounts of progesterone • Progestins • 6-8 weeks : corpus luteum produces progesterone • thereafter : placenta produces progesterone (30-40 times more) • Placenta does not synthesize cholesterol and depends on maternal supply • Estrogens • E1, E2, E3 • The major hormone is E3 synthesized by feto-placental function • Placental lactogen (PL):chorionic somatomammotropin/ placental growth hormone

25. Steroid metabolism by the fetal-maternal unit

26. Mammary gland development • E2 (for ductal growth) • Progesterone (alveolar proliferation) • Additional actions of prolactin, glucocorticoids, insulin • Progesterone inhibits milk production and secretion in late pregnancy • Lactation : prolactin and oxytocin • The production of oxytocin and it’s receptors are stimulated by estrogens and inhibited by progesterone

27. Menopause • Weak estrogen ,E1, produced by aromatization of androstenedione • Marked increases of LH and FSH • Estrone is not always able to prevent the atrophy of secondary sex tissues and osteoporosis

28. Pathological States • Hypogonadism • Gonadal dysgenesis • Polycystic ovary syndrome : overproduction of androgens ( hirsutism, obesity,irregular menses,impaired fertility) • Hypergonadism • Granulosa-theca cell tumors • Persistent trophoblastic tissue : benign hydatiform mole and its malignant form , choriocarcinoma • Infertility • Elevated testosterone,decreased SHBG • DHEA sulphate :adrenal ;androstenedione : ovary