Gonad Hormones : Female Prof.Dr.Gülden Burçak

Ovary : produces female sex hormones and female germ cells

  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

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

(+) Feedback of gonadal steroids on pituitary   E 2 > 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 E 2   Chronic stress or profound weight loss can disrupt the pattern of GnRH secretion and lead to anovulation and amenorrhea.

In childhood : HPA remains highly sensitive to (-) feedback effects of gonadal steroids In puberty : adrenarche, decreased sensitivity of HPA to (-) feedback and gonadarche, increased E 2, 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

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

Aromatization of androgens in granulosa cells (also some estradiol in corpus luteum)   Three hydroxylation steps, O 2 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,Δ 5,4 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

Ovarian nonsteroidal hormones Cytokines, growth factors and neuropeptides Inhibins : multifunctional glycoproteins A and B   Inhibin A(αß A ) is low in early follicular phase, high in the luteal phase ;inhibin B(αß B ) 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 gonadotrop es increases FSH secretion

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

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.

Metabolism of ovarian steroids In the liver,estradiol (E 2 ) and estrone(E 1 ) are converted to estriol (E 3 ) and conjugated with glucuronic a. or sulfate; excreted by the kidney   Oral estrogens are effective because 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

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

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

Menstrual cycle-Follicular phase   A particular follicle begins to enlarge under the influence of FSH   E 2 and LH rise, E 2 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 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

Menstrual cycle-Luteal phase   The granulosa cells of the ruptured follicle luteinize and form the corpus luteum   Corpus luteum produces progesterone and some E 2   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.

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   E 1, E 2, E 3   The major hormone is E 3 synthesized by feto-placental function Placental lactogen (PL): chorionic somatomammotropin/ placental growth hormone

Steroid metabolism by the fetal- maternal unit

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

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

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