2 Sexual Differentiation

1. 2 Sexual Differentiation Becoming a female

2. The female pathway is the default setting In the absence of SRY, the primitive gonad automatically differentiates as female. In the absence of testosterone (or other androgen), the Wolffian system deteriorates. In the absence of Mullerian inhibiting factor, the Mullerian structures automatically form the Fallopian tubes, uterus and inner 2/3 of the vagina.

3. In the absence of androgen, the external genitalia differentiate as female

4. The X chromosome and disorders of chromosomal sex • XO: Turner’s syndrome – female gonadal sex and female body plan – ovaries do not differentiate beyond the primitive streak stage – no growth spurt, no fertility, feminizing puberty and sustained feminine characteristics must be sustained by exogenous estrogen. • XXX “superfemale” – essentially normal female sexual differentiation but reduced fertility.

5. The adrenogenital syndrome in XX genotype • Excess DHEA is present during fetal life – various causes including 21 hydroxylase deficiency in fetus or mother, maternal adrenal tumor, maternal hyperadrenalism • Generally, the extra androgen comes too late to preserve the Wolffian system, but can result in partial or total masculinization of the external genitalia • A somewhat masculinized body style is typical – some investigators have associated this with a “tomboy” set of behaviors.

6. Female puberty • Increase in secretion of Gnrh leads to increase in LH and FSH secretion – menarche – menstrual cycles begin. • At puberty, ovaries contain about 400,000 primary follicles, each containing a primary oocyte arrested at 1st meiotic metaphase. • Each cycle leads to initiation of maturation of about 1,000 primary follicles. Of these, only one or two (in humans – more in animals that typically have multiple births) reach the stage of ovulation – the others are eliminated by a process called atresia.

7. The mean age of menarche in N. European populations has fallen steadily over the past two centuries

8. Maturing Follicles are the sources of ovarian steroid • During the period of follicle maturation (follicular phase) in each cycle, theca cells (outer layer; homologues of Leydig cells, so controlled mainly by LH) of each follicle produce androgen (androstenedione). • Androgen is exported to the granulosa cells (inner layer; homologues of Sertoli cells, so controlled mainly by FSH) for conversion to estradiol, the major form of estrogen secreted by the ovary. • After ovulation, the remnants of the follicle form a corpus luteum that secretes both estradiol and progesterone during the luteal phase of the cycle.

9. Ovarian sterol biosynthesis involves collaboration between theca cells and granulosa cells LH FSH Granulosa cell Theca cell cholesterol cholesterol progesterone androstenedione androstenedione estradiol

10. Effects of estrogen at puberty • Establishes female pattern of body fat deposition, bone growth and body hair • Stimulates growth of external and internal genitalia • Stimulates breast maturation, particularly the ductal system • Stimulates growth of uterine endometrium, particularly during the follicular phase of the menstrual cycle

11. The female cycle takes place on multiple anatomic levels • Ovarian: follicular – luteal • Plasma: levels of FSH, LH, estradiol, progesterone and inhibin • Uterine endometrium – proliferative – secretory - menstrual • Cervical/Vaginal: impenetrable mucus/acid pH – watery mucus, alkaline pH • Behavioral: humans: subtle sexual interest variations over the cycle. Other mammals: estrogen leads to estrus behavior.

12. The ovarian cycle

13. The endocrine picture over the menstrual cycle

14. The control relationship between hypothalamus, ant. pituitary and ovary changes over the cycle • A complete cycle can occur if the hypothalamus just releases Gnrh in regular pulses – therefore the hypothalamus does not organize the cycle. • The pituitary can organize the cycle but to do so it must have a dialogue with the ovary. • As estrogen levels rise, the pituitary switches from decreasing LH and FSH release in response to estrogen (negative feedback) – to increasing FSH and LH release in response to estrogen – a positive feedback that leads to a spike of gonadotropins as the follicle matures.

15. Control of ovarian function Hypothalamus Gnrh inhibin Ant.pituitary estradiol FSH LH Ovaries Follicularization Estrogen secretion Ovum maturation

16. Ovulation In the human pattern,ovulation is triggered around day 14 of the cycle by a sharp rise in plasma gonadotropins The oocyte is surrounded by a corona radiata of follicular cells

17. The Uterine Endometrium

18. The Uterine cycle • The endometrium consists of a functional layer that contains stem cells, and a differentiated decidual layer that can be shed periodically • During the follicular phase of the ovary, estradiol causes the uterine lining to proliferate and thicken. • During the luteal phase, the addition of progesterone causes the endometrium to develop additional vascular elements, and spiral glands that secrete nutrients (uterine milk) into the uterine lumen – during this phase, the endometrial conditions are ideal for implantation of a zygote. A state of pseudopregnancy exists in this period. • Shedding of the decidual layer – menstruation - results from the sudden drop in plasma levels of estradiol and progesterone as the corpus luteum becomes a corpus albicans.

19. Menopause • In humans, menopause occurs in the age range of 45-55 years. Menopause is not a common phenomenon in non-human mammals. • At menopause, it appears that the initial stock of primary follicles has been exhausted – a dominant hypothesis argues that follicle exhaustion determines the timing of menopause. • However, reduction of cycle number by use of hormonal birth control does not delay menopause, so follicle atresia must steadily eliminate follicles whether cycling is occurring or not. • The onset of menopause is accompanied by a large rise in the plasma levels of gonadotropins, arguing that the hypothalamus and pituitary do not initiate menopause by shutting down ovarian function

20. Hormonal contraception • Site and mechanism of action of hormonal contraceptive depends on the hormonal constituents and their dosages (i.e. estrogen. estrogen+progesterone, progesterone only) • Potentially, exogenous steroids could interfere with: • Gnrh secretion • Gonadotropin secretion • Egg/sperm transport in Fallopian tube • Vaginal/cervical environment • Implantation of zygote