PHYSIOLOGY OF THE FEMALE REPRODUCTIVE TRACT Simple Framework: Hypothalamus secrete Gonadotropin releaseing hormones - Goes down the

e anterioir pituitary gland o Release FSH and LH - From anterior pituitary gland -> goes down to effect certain changes in the ovary and produce steroid hormones - Estrogen and progesterone o Has an effect of lining of endometrium and growth of the ovary HYPOTHALAMO- PITUITARY OVARIAN AXIS (HPO AXIS) 1. Hypothalamus o GNRH 2. Pituitary o LH, FSH 3. Ovary 4. Uterus Positive Feedback mechanism: days 12-14 of menstrual cycle Negative Feedback mechanism: operates throughout most of the cycle

Gonadotrophin levels are very sensitive o Very sensitive to levels of estradiol in circulation (negative feedback) Subsequently decline by 1 yr of age Remain very low until 6-8 years of age Begin to increase in 10-11 years of age Onset of puberty o Prior to the onset of puberty, 2 events occur: Reactivation of gonadotropin synthesis and secretion Decreased sensitivity to negative feedback of estrogen

Infancy, Childhood and Prepuberty - Hypothalamus, anterior pituitary gland and gonads of the fetus, neonate, infant and prepubertal child - Functional - Capable of secreting hormones in adult concentrations Present and functional at the time of c development of fetal stage, neonate, etc. Function is not yet full blown During fetal life: o FSH/LH reach adult levels until midgestation o Due to high levels of pregnancy steroid hormones, levels fall and remain low At birth o Prompt increase in gonadotropins o Causes transient estradiol secretion for 2-4 months Equivalent to midfollicular phase of the cycle Follicular maturation and atresia Revert back to quiescent phase because the baby is cut-off to the suppressive effects of steroids when it is still in utero

PUBERTY - Endocrine events occurring between ages 10-16 o Increased pulsatile patterns of LH during sleep o Similar pulses of less amplitude occurring throughout the 24 hour day o Episodic peak of estradiol occurs o Maturation of the positive feedback relationship between estradiol is established Ovulatory cycles are established - An evolving sequence of maturational steps o Gonadarche increase in gonadal estrogen Estrogen coming from the ovaries (GONADS) Breast development, female fat distribution and vaginal and uterine growth o Adrenarche increase in adrenal androgen Pubic and axillary hair growth o Growth spurt o Menarche sufficient gonadal estrogen levels are reached Endometrium proliferation First menses occurs 2 months from breast budding Fetal life until birth - Oogenesis begins in fetal life o Development of egg cell - Germ cells (oogonia) increase in number by mitotic division - 600, 000 (2nd month) - 7 million (5th month) - GnRH levels are high causing elevated gonadotropins during midgestation o At midgestation they FALL - Placental estrogen is also high - Oogonia are transformed to primary oocytes as they enter the 1st meiotic division - 2-4 million primary oocyctes at birth

Before birth, development of HPO axis and negative feedback of high estrogen -> decrease Gonadotropins

Birth to puberty - Primary oocytes are arrested at the diplotene stage of the 1st meiotic division - Oocytes stay quiescent and some undergo atresia - 400,000 (menarche) - Gonadotropin independent - At birth, withdrawal of maternal estrogen -> increase in gonadotropins (higher than pubertal values) -> diminished until 4 years old (CNS inhibits GnRH release) - When does Gonadotropin secretion usually begin? o Increased synthesis of gonadotropin Gonadotropin Releasing Hormone (GnRH) - Peptide hormone - High molecular weight of 200,000 300,000 daltons - Produced by the hypothalamus - Binds to specific receptors on the surface of the anterior pituitary GnRH - Secreted in a pulsatile manner - Half-life of 2-4 minutes - Amplitude and frequency of secretion varies throughout - Pulsatile secretions of GnRH results in the gonadotropin surge -> ovulation - Increasing or decreasing the frequency OR is given continuously will inhibit the gonadotropin surge because the receptors are saturated - GnRH secretion is regulated by: o GnRH itself The ovarian GnRH Drugs affecting secretion - Methyldopa and alpha p tyrosine o Can block synthesis of dopamine - Reserpine and Chlorpromazine - Tri-cyclic antidepressants - Propanolol, Phentolamine, Cyproheptadine and Haloperidol GONADOTROPINS - Glycoproteins of high molecular weight - Composed of alpha and beta subunits by disulfide bonds - Similar in structure to the alpha subunit 1. Luteneizing Hormones

Half-life of 30 mins Acts primarily on the theca cells to induce steroidogenesis 2. Follicle stimulating hormone - Half-life of 3.9 hours - Acts primarily on the granulose cells to stimulate follicular growth

GONADOTROPINS: TWO CELL HYPOTHESIS OF ESTROGEN PRODUCTION - LH main function is the production of ANDROGENS - FSH granulose cells - > enzyme AROMATASE - > cAMP -> Estrogen - Not independent of each other - Synergistic in effect in helping to produce estrogen OVARIES - Site of steroids production - Estradiol o Biologic form - Progesterone - Androstenedione Estrogen effect - Ratio of uterine corpus to cervix is 1:1 o Changes as female mature Progesterone Effect OVARY: Non sterodial hormone production - Activin - Inhibin

Effects of hormones on specific reproductive factors - Folliculogenesis o Recruitment of follicles o Selection and maturation of a dominant follicle o Release of follicle - OVULATION - Uterine endometrial histology o Cyclic histologic and morphologic changes

UTERINE ENDOMETRIAL HISTOLOGY - Stratum Basale o Does not change in response to hormone o Does not desquamate not released as menstrual blood - Stratum functionale o Grows throughout the menstrual cycle in response to estrogen and progesterone o Subdivided to compactum and spongiosum

Myometrium - Stratum basale and stratum functionale Menstrual cycle - Estimated blood loss of 80ml per menstrual cycle MENSES - Ischemia Day 3-7 - FSH and estradiol increase because of growing follicle o Start of uterine lining Day 7-11 FSH - Ovulation - To select a follicle to mature properly - Stop producing FSH: NEGATIVE FEEDBACK - Granulosa cells are very active - Estradiol begin to increase - Estradiol causes continuing proliferation Day 12-19 - Time of ovulation - Reached its peak amounts - Surge in LH o Dictates the rupture of the dominant follicle to release the egg - Peak of estradiol dictates the LH surge to release the egg - Estradiol o Thickened linings Day 18-23 (14-18) - Shift of steroid production of corpus luteum - Fertilization - Corpus luteum now produce PROGESTERONE - Estradiol becomes a steady state SECRETORY PHASE - time of menstrual phase Only thing that will interfere menstrual cycle is PREGNANCY AGING AND MENOPAUSE - Heralds puberty increased amplitude of pulses during sleep o 1sT ENDOCRINOLOGIC SIGN OF PUBERTY -