1. Chp 3: Hormonal Influences on Female Sex Behavior Female sex behavior can be divided into two components: precopulatory behavior: AKA “proceptive behavior”--the female approaches a male and shows solicitatious behavior to get the male to engage in copulation 3 components to proceptive behavior: (female rat) –approach –orientation: female presents anogenital region to male; “ear wiggling”-- rapid movement of head (serves to exicte male) –runaway: “hopping and darting”--hopping and rapid flight away from the male copulatory behavior: display of lordosis (AKA “receptive behavior”) –immobility –arching of the back with an elevation in the rump & head region; can also include movement of tail laterally –.

2. Quantification of Proceptive and Receptive Behaviors It may be important to determine the degree of proceptivity or receptivity of a given female, especially when looking at interactions between individuals. Ex. quantification of lordosis behavior –strength of lordotic posture –frequency of lordosis –duration of lordosis lordosis quotient is calculated as a measure of a female’s receptivity –[# lordotic postures by female]/[10 mounts by male] X 100 = LQ –if a female shows 5 lordotic postures to 10 mounts by male, then LQ=50; this would be considered a moderately receptive female.

3. Hormonal Influences on Female Sex Behavior Estrogen and progesterone play an important role in female sex behavior. Considering the female rat as a model: estrogen: –enhance “attractivity” of the female to the male (increasing production of pheromones and vocalizations) –induce a GnRH surge that will lead to an LH surge and subsequently ovulation estrogen and progesterone: –increase female’s willingness to approach a male and to show solicitious behavior –these hormones will “couple” sex behavior with ovulation progesterone has biphasic effects on female sex behavior: –initially, increases in progesterone will stimulate female sex behavior –prolonged exposure to progesterone will inhibit female sex behavior

4. Hormonal Influences on Female Sex Behavior In many mammalian species, females show precopulatory and copulatory behaviors at specific times during their reproductive cycle. Definitions: estrus: refers to the day in which ovulation occurs behavioral estrus: refers to the period of time during which female shows precopulatory and copulatory behaviors (AKA--“behavioral heat”) estrus cycle: series of ovarian events that determines when an animal comes into estrus In females that ovulate spontaneously, the duration of an ovarian cycle can vary: –4 days: mice, rats and hamsters –16 days: guinea pigs –28 days: humans

5. Ovarian Cycle There are 3 main phases of ovarian cycle: follicular phase: series of hormonal events: GnRH-->LH & FSH-->estrogen –FSH stimulates primary follicles to enlarge and differentiate into inner granulosa cell layer and an outer thecal cell layer; oocyte (egg) may also complete development –LH and FSH act together to produce estrogen: LH stimulates thecal cells to produce androgens, and androgens are converted to estrogens in granulosa cells via aromatase; FSH increases aromatase activity in granulosa cells –lasts 2-3 days in rodents and 10-14 days in humans periovulatory phase: –as follicle matures, rate of estrogen secretion increases –in female rats, increase in estrogen will stimulate a GnRH surge followed by an LH surge-->LH surge will cause the ovarian follicle to rupture-->release the egg; a rise in LH also induces a preovulatory surge of progesterone release from ovaries –lasts about 12 hours in most rodents; in humans it occurs over a period of 1-2 days

6. Ovulation and GnRH Surge in Rats: Ovulation: as follicles develop in ovary –increasing levels of estrogen are released –in female rats, increases in estrogen lead to a GnRH surge (positive feedback) –GnRH surge leads to LH surge –LH surge leads to ovulation male rats are unable to show a GnRH surge in response to increases in estrogen GnRH Neuron HYPO ANT PIT OVARY FSH LH Estrogen GnRH + GnRH: gonadotropin-releasing hormone FSH: follicle stimulating hormone LH: luteinizing hormone

7. Ovarian Cycle luteal phase: –once the follicle has ruptured and expelled its egg into Fallopian tube (oviduct), the remaining follicle may be transformed into the corpus luteum –corpus luteum secretes progesterone which is important for: 1) implantation of the egg into the uterine wall, and 2) maintenance of pregnancy –in some species, corpus luteum is “spontaneously functional”, in other species, vaginal- cervical stimulation during copulation is required for formation of corpus luteum –length varies depending on species; in humans, lasts 10-12 days menstrual phase: (species dependent) –see uterine bleeding in species that have long ovarian cycles (primates) –during luteal phase, estrogen and progesterone prepare uterus for implantation –if the egg is not fertilized, then no embryo will implant into uterine wall, the corpus luteum will regress (die) –drop in estrogen and progesterone levels will lead to sloughing off of the uterine wall (endometrium)--”uterine bleeding”

9. Female Rat Estrous Cycle day 1--metestrus: –early: ovarian hormone secretion is relatively low –late: start of follicular activity day 2--diestrus: –follicles continue to develop, see significant increases in estrogen levels day 3--proestrus: –early: see further increases in estrogen –late: estrogen levels peak mid-late proestrus; the rise in estrogen stimulates GnRH and LH surges; the rise in LH will also stimulate preovulatory rise in progesterone day 4--estrus: –early: ovulation (resulting from increases in estrogen and LH), and behavioral estrus--proceptive and receptive behaviors (resulting from increases in estrogen and progesterone) –late: declining levels of estrogen and progesterone depends on whether female engages in copulation follicular phase periovulatory phase luteal phase

10. Formation of the Corpus Luteum Spontaneously Functional: following ovulation, the corpus luteum forms and secretes progesterone (and estrogen) for several days –Ex: humans Not Spontaneously Functional: corpus luteum will not form unless female engages in copulation –Ex: rats critical stimulus--intromissions (insertion of penis into vagina by male) will stimulate a neuroendocrine reflex in the female leading to release of PRL which then acts to form the corpus luteum PRF Neuron HYPO ANT PIT OVARY PRL progesterone PRF + PRF: prolactin releasing factor PRL: prolactin follicle egg “corpus luteum” forms vaginocervical stimulation spinal cord PRL Neuroendocrine Reflex

11. Hormones and Female Sex Behavior How do gonadal steroids affect the nervous system to stimulate sex behavior? Female rat as a model: both estrogen and progesterone are needed to stimulate female sex behavior--if you ovariectomize (OVX) a female rat, she will not show proceptive nor receptive behaviors if you OVX a female rat + administer estrogen for 1 to 2 days + single injection of progesterone-->sex behavior will occur 4 hours after the progesterone injection (“activational effects” of gonadal sterodis) –rise in estrogen primes the brain to respond to progesterone –rise in progesterone times the onset of behavioral estrus ventromedial nucleus of the hypothalamus (VMH) plays an important role in hormonal modulation of lordosis estrogen and progesterone act, in part, at the VMH to stimulate the display of lordosis in response to mounting by a male

12. Ventromedial Nucleus of the Hypothalamus VMH is critical for hormone-mediated lordosis behavior –bilateral lesions of VMH can reduce or eliminate lordosis estrogen and progesterone act at the VMH to activate female sex behavior –if OVX an adult female rat, lordosis behavior will not be shown –if you give estrogen for 2 days followed by a single injection of progesterone, lordosis behavior will be shown 4 hours later –if you implant estrogen capsules within the VMH and administer progesterone systemically, lordosis behavior will be shown (estrogen acts specifically within VMH to stimulate lordosis; this is also true for progesterone) mechanism: (genomic) –increases in estrogen lead to increases in ER within lateral VMH –estrogen binds to ER induce expression of PR (genomic mechanism) –rising progesterone levels then bind to PR induce the expression of other proteins that serve to activate lordosis (genomic mechanism) –know that protein systhesis is critical to facilitation of lordosis--1) administration of a protein synthesis inhibitor inhibits lordosis, and 2) time- frame for effects to be seen takes 3-4 hours –neurons within VMH project to PAG: changes in synthesis of proteins in VMH neurons leads to an increased state of excitability of neurons within the PAG that control motoneurons within brainstem and spinal cord

13. Ventromedial Nucleus of the Hypothalamus What proteins are synthesized within the VMH that can lead to an increased state of excitability of neurons within the PAG? Recent evidence suggests: evidence that estrogen and/or progesterone can increase the number of oxytocin receptors within VMH-->administration of oxytocin can stimulate female sex behavior (specific to VMH?) –oxytocin may facilitate lordosis by altering other responses such as decreasing aggressive behavior or increasing pair-bonding evidence that estrogen can increase the number of acetylcholine receptors within VMH-->administration of acetylcholine within VMH can stimulate female sex behavior (this effect is also seen other brain areas) evidence that estrogen can also increase a 70,000 MW protein--an isoform of phospholipase C that is transported to the midbrain periaqueductal gray How do these changes lead to increased excitability of PAG neurons? not presently known

14. Periaqueductal Gray PAG--via input from VMH--is critical for hormone-mediated lordosis behavior –lesions of the PAG can block display of lordossis PAG integrates hormonal and sensory inputs: –the PAG must receive excitatory input from VMH (critical)-->increased excitability of PAG neurons –when a male mounts a female, somatosensory information will be relayed to the PAG to activate lordosis –the PAG will excite neurons within the reticular formation of the brainstem (medulla) –reticular formation integrates sensory and motor responses (within the spinal cord) for the display of lordosis--immobility, arching of head and rump and movement of tail laterally –PAG also contains ERs, so estrogen may also act at the PAG to facilitate the display of lordosis

15. Medial Preoptic Area Neurons within MPOA can have inhibitory and facilitatory effects on lordosis. Inhibitory: estrogen-responsive neurons in MPOA project to the VMH and PAG neurons within the MPOA have inhibitory effects on lordosis –lesion neurons within dorsolateral MPOA-->facilitation of lordosis –stimulate neurons within dorsolateral MPOA-->inhibition of lordosis estrogen can act to decrease electrophysiological activity of MPOA neurons current theory: estrogen acts at VMH to increase “excitatory drive” on lordosis, while decreasing “inhibitory tone” by decreasing activity of neurons within MPOA Stimulatory: GnRH neurons are also present throughout MPOA (located more medially) GnRH secretion into median eminence (neurohormone) will lead to follicular development, estrogen secretion, preovulatory rise in progesterone, LH surge and ovulation GnRH can also be secreted within brain (neurotransmitter); GnRH receptors are present within VMH and PAG, and administration of GnRH into VMH and/or PAG can facilitate lordosis

16. Progesterone Progesterone has biphasic effects on sex behavior in the female rat: progesterone interacts with PRs to stimulate the display of lordosis (as well as the display of proceptive behaviors) prolonged exposure to progesterone can inhibit sex behavior Mechanism of inhibitory effects: progesterone can lead to a decrease in the number of PRs and ERs (considered a refractory state) It is essential that the elevations in estrogen and progesterone drop to low levels so that elevations in these two hormones can effect changes in protein synthesis within the brain to effect changes in behavior.

17. Dopamine Dopamine is a neurotransmitter synthesized within two main cell groups: substantia nigra: –dopaminergic neurons project to the basal ganglia to control general locomotion and execution of stereotyped movements ventral tegmental area: –dopaminergic neurons project to nucleus accumbens to control motivated behavior Background information: estrogen can facilitate release of dopamine and hence dopamine-mediated processes further, it is known that dopamine is released within the basal ganglia and nucleus accumbens of female rats during sex behavior Thus, estrogen-enhanced release of dopamine within the basal ganglia and nucleus accumbens most likely acts to promote proceptive behaviors. Note: dopaminergic activity is not believed to be important for the display of lordosis.

18. Species Differences in Periovulatory Period: In rats: as follicles mature and grow in size, estrogen levels increase increase in estrogen leads to a GnRH surge, an LH surge, and the LH surge leads to ovulation (deterministic model) the rise in LH also stimulates secretion of progesterone from the ovary preovulatory rise in progesterone acts to couple behavioral estrus with ovulation (estrus) if mating occurs, the corpus luteum will form and secrete progesterone (luteal phase) In primates: as follicles mature and grow in size, estrogen levels increase increase in estrogen leads to increased sensitivity of the pituitary to GnRH, the pituitary secretes more LH to a given amount of GnRH (LH surge), and the LH surge leads to ovulation (permissive model) there is no preovulatory rise in progesterone the corpus luteum will form spontaneously and secrete progesterone during the luteal phase

19. Species-Specific Patterns--Sex Behavior & Ovulation: spontaneous ovulation –a series of hormonal events lead to the occurrence of ovulation –Ex: rats (hormonal events also time the occurrence of behavioral estrus) –Ex: humans induced ovulation –behavioral estrus occurs in spontaneous cycles, but ovulation does not occur without copulation –Ex: rabbits, cats and ferrets induced estrus and ovulation –both behavioral estrus and ovulation are induced by specific stimuli external to the female –Ex: prairie vole

20. the ovaries produce waves of follicles, and follicles secrete estrogen increasing levels of estrogen stimulate behavioral estrus – progesterone is not needed to stimulate sex behavior vaginocervical stimulation (via intromissions from male) will activate a neuroendocrine reflex resulting in GnRH release GnRH release will lead to LH surge and ovulation subsequent production of progesterone will maintain pregnancy if necessary GnRH Neuron HYPO ANT PIT OVARY LH GnRH GnRH: gonadotrophin releasing hormone FSH: follicle stimulating hormone LH: luteinizing hormone follicle “ovulation” vaginocervical stimulation spinal cord GnRH Neuroendocrine Reflex LH FSH estrogen stimulate sex behavior Induced Ovulation

21. a female is reproductively inactive until exposed to a male a male pheromone stimulates GnRH release (neuroendocrine reflex) –GnRH release stimulates FSH and LH release, follicular development and secretion of estrogen increasing levels of estrogen stimulate behavioral estrus vaginocervical stimulation (via intromissions from male) stimulates further GnRH release –GnRH release will lead to LH surge and ovulation after ovulation, progesterone will maintain pregnancy if necessary GnRH Neuron HYPO ANT PIT OVARY LH GnRH + GnRH: gonadotrophin releasing hormone FSH: follicle stimulating hormone LH: luteinizing hormone follicle “ovulation” vaginocervical stimulation spinal cord GnRH Neuroendocrine Reflex--twice LH FSH estrogen stimulate sex behavior Induced Estrus &Ovulation pheromone