Gonad Hormones : Gonad Hormones : FemaleFemale

Prof.Dr.Gülden BurçakProf.Dr.Gülden Burçak

2011-20122011-2012

Ovary : produces female sex Ovary : produces female sex hormones and female germ hormones and female germ

cellscells

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

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.

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

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, 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

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

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 (E2) and estrone(E1 ) are converted to estriol (E3) 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

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

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.

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

Steroid metabolism by the fetal-Steroid metabolism by the fetal-maternal unitmaternal 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