Gonads:- According to both sexes, the gonads are two: Ovaries (female) secrete: –P–Progesterone –O–Oestrogen: It is the end product that can control secretion of hypothalamus and pituitary. Testes (male): imp for the production of testosterone Secretion of these glands is controlled by hypothalamic-pituitary gonadal axis (HPG axis).

Female sex hormones: Levels of LH and FSH (therefore oestrogen and progesterone) are different according to the period of menstrual cycle phase: A typical cycle consists of 28 days; Follicular phase, (day 1 until day 14). Ovulatory phase (48 hrs after day 14) and Luteal phase: The remaining time until the end of the cycle. At the first day (time of bleeding), there is low levels of oestrogen and progesterone. This low level of oestrogen results in loss of negative feedback mechanism with gradual increase in LH and FSH. FSH will act on several ovarian follicles (about 5 to 6), but it results in development of a single follicle (Graafian follicle), which becomes mature and prepares the ovum.

LH at the same time stimulates secretion of oestrogen from developing follicles. This oestrogen increases to a peak level at 12 hrs before the day 14. This peak of oestrogen undergoes positive feedback stimulation of LH secretion and results in peak increase in LH level. This is called LH-surge which is critical for ovulation. After ovulation, the empty follicle is called corpus luteum or yellow body, which releases progesterone and oestrogen. Progesterone prepares the uterus for implantation of fertilized ovum if present. This is the luteal phase. If there is no implantation, the endometrium shedding occurs and the cycle takes place again.

Disorders of the gonads: Primary ovarian failure: due to defect in ovaries → low oestrogen levels → high levels of LH and FSH (caused by loss of negative feedback mechanism) e.g. menopause Secondary ovarian failure: due to diseases in hypothalamus (no GnRH) or pituitary result in → low levels of LH and FSH → low levels of oestrogen e.g. panhypopituitarism. Both of these conditions can result in amenorrhoea and infertility.

Male sex hormones: LH stimulates Leydig's cells of testes to secrete testosterone. This hormone is responsible for male secondary sex characteristics, and gives male characters in general. It inhibits gonadotropin secretion by negative feedback inhibition, similar to that of ovarian hormones in females. If there is testicular failure due to any cause it is called primary endocrine disease, where there is low level of testosterone, resulting in loss of negative feedback mechanism, with stimulation of LH secretion, so the level of LH will be very high in blood. But if there is hypothalamic or pituitary diseases, level of LH and FSH are low, so level of testosterone is also within low limits this is secondary testicular failure (secondary endocrine disease).

FSH stimulates spermatogenesis and its level is not controlled by testosterone, but by another factor called inhibin, which is secreted from Sertoli's cells (in testes) or from mature sperm. Therefore if there is low FSH this will result in oligospermia or azoospermia and infertility in males The indicators of defect in spermatogenesis are high levels of FSH (in blood), with very low level of inhibin (glycoprotein secreted by seminiferous tubules).

Types Sex Hormones: Androgens: These are a group of 19C steroids, required for differentiation of male genital tract and development of secondary male sex characteristics. They also influence muscle bulk, bone mass and sexual performance in males. In females, androgens act as precursors of oestrogen (18C steroids) and they are important in low levels for normal libido in female.

There are several types of androgens: Testosterone (most important androgen in blood): In male it is secreted from Sertoli cells, whilst in females 50% testosterone is derived from peripheral conversion of androstenedione, 25 % originate from ovaries and 25% from the adrenal glands. Structurally, testosterone is a 19C steroid and has unsaturated bond between C 4- and C 5- and a ketone group at C 17. Testosterone is converted to a more potent steroid called dihydrotestosterone (DHT) by the enzyme 5- reductase, which presents in prostate, genital skin and seminal vesicles.

Androstenedione: produced from testosterone in peripheral tissues, it may also be produced by adrenal or ovaries, or peripheral conversion of plasma dehydroepiandrosterone (DHEA). Both are weak androgens they act more as pre- hormones for testosterone. Biosynthesis occurs in testis and adrenals by two pathways: Pregnenolone is transformed to 17- hydroxypregnenolone and then to DHEA, later on to androstenedione and testosterone. Pregnenolone to progesterone, then to androstenedione. This pathway is more active.

Metabolism In blood, testosterone is bound to plasma protein, sex hormone-binding globulin (SHBG). In women, only 1% while in males 3% of total testosterone is free, which is the biologically active form. The main metabolites of androstenedione and testosterone are produced by reduction of ketone group at carbon 3- and also carbon 7- positions. Most of these androgens are converted irreversibly to 17- keto- steroids which conjugate with sulphuric acid and glucoronic acid, excreted as water-soluble substances in urine.

Several methods have been used to detect androgens in serum and urine, the main one is radioimmunoassay (RIA) and enzyme-linked fluoroimmunoassay (ELFIA). Normal range in male adult is (3-10) ng/mL, while in females it is ( ) ng/mL. The highest level of testosterone in males occurs in the morning and decreases to 25% in evening. Slow and progressive decline occurs after 5th decade of life. In females, highest level is during puberty or 1 to 2 days at mid cycle. Clinical disorders: there are two types of disorders that affect androgen level, depending on the tissue affected; these are primary or secondary endocrine diseases.

Progesterone: during menstrual cycle, progesterone in conjugation with oestrogen regulates function of sex characteristics. It is important for preparing uterus for implantation and maintenance in pregnancy. In non- pregnant women, progesterone is secreted from corpus luteum whilst during pregnancy it is secreted from placenta. Minor sources also occur in adrenal cortex and testes in male. Structurally, progesterone is a 21C steroid contains keto group at carbon 3-, double bond between carbon 4- and carbon 5-. Both of these structural characters are essential for progesterone activity. Synthetic compounds called 19-nortestosterone that is widely used as an oral contraceptive, which is more potent than progesterone itself.

Metabolism: the production of progesterone in ovaries occurs the same as for steroidogenesis in adrenal cortex, in which acetate converts to cholesterol, then enters through the pathway of pregnenolone. In ovarian tissue the precursor is LDL cholesterol, from which the secretion of progesterone is under the control of LH. In blood, progesterone is bound to CBG (it doesn't have a specific binding protein). The free level is 10-20% of total, which remains constant throughout the normal menstrual cycle. Its peak level occurs at luteal phase, reaching 30mg/day (in non-pregnant women). At third trimester (last 3 months of pregnancy), the level reaches 300mg/d.

Inactivation of this hormone occurs through two procedures: Reduction of pregnenidiol (conjugated form with glucoronic acid) then excreted out as water-soluble substance in urine. This urine pregnenidiol is used as index of endogenous production of progesterone. Conjugated with sulphuric acid and excreted outside the body.

Clinical significance: during follicular phase of cycle, serum level is 1ng/mL, but after ovulation, production of PRG from corpus luteum increases to a maximum of (10-20) ng/mL in the fourth to seventh day of luteal phase. This level remains elevated for four to six days, and then decreases suddenly to baseline level at about 24hr before bleeding. Since the increase or decrease in PRG level is related to corpus luteum (and so ovulation), we can use PRG as indicator of ovulation. If the level of PRG at luteal phase is similar to that of follicular phase, or the summation of three consequent measures at the last seven days of cycle, is less than 15ng/mL, this indicates that the cycle is un-ovulatory cycle, which could be the cause of infertility.

Oestrogen: responsible for development and maintenance sex hormones and secondary sex characteristics of females. Regulation of menstrual cycle, and maintenance of pregnancy, Shared with PRL and PRG in breast development for lactation but it Inhibits milk secretion, as it inhibit prolactin action on lactating glands (so it can be used clinically for this purpose). Most estrogens are produced in corpus luteum and (during pregnancy) from placenta.

Oestradiol (E2) is the most potent estrogen. Structurally, estrogen consists of an 18C and has the following features: 1.Presence of aromatic (phenol) ring A 2.Presence of hydroxyl group at C-17 (C-16 in case of oestriol). Phenolic hydroxyl group at C-3 gives the compound its acidic properties. The phenol ring A and oxygen at carbon 17- are essential for biological activity. Any substituents at other positions will diminish the feminizing activity of this hormone.

Biosynthesis: the three classes are produced by ovarian tissue which has active aromatase system that converts androgens to oestrogens. In menopausal women (ovarian failure), the main source of oestrogen is from peripheral adrenal conversion of androstenedione to oestrone¹. The major site for conversion is adipose tissue, explaining high levels of oestrone in post-menopausal women and also the uterine bleeding that occurs in such women. In blood, oestradiol² is strongly bound to SHBG and loosely to albumin, while only 2-3% is free (active).In contrast, oestrone is almost always bound to albumin. During pregnancy the major source of oestrogen is the placenta, which secretes large quantities in milligrams; the main oestrogen produced is oestriol³ (during pregnancy).

Metabolism: oestradiol forms reversible redox system with oestrone, which is metabolised through two pathways; 2- hydroxylation pathway, with production of catecholestrogen and 16  -hydroxylase pathway with formation of oestriol. Some pathological conditions, such as in hyperthyroidism, the 2-hydroxylation pathway is increased. During liver disease or hypothyroidism the reverse occurs. Oestrogen is inactivated in liver and excreted in urine (like all other steroids).

Clinical significance: oestradiol is almost always secreted from ovaries, therefore is essential for evaluation of ovarian function. Oestriol is of limited diagnostic use, but we use it in diagnosis of post-menopausal bleeding and menstrual dysfunction. Oestriol is only used during pregnancy to evaluate the foeto-placental dysfunction.