All Phenotypes Fshr<+> MGI Mouse

mortality/aging

neonatal lethality, complete penetrance ( J:140008 )

• all pups (if any) delivered by 12-mo-old heterozygous females die within 18-48 hrs after birth

postnatal lethality, incomplete penetrance ( J:140008 )

• success at first weaning (number of surviving pups by P21) in crosses between 3-mo-old heterozygous females and wild-type males is reduced by 25% relative to age-matched wild-type females

• in crosses between 7-mo-old heterozygous females and wild-type males the index of weaning success declines to ~43% versus ~71% in age-matched wild-type controls

premature aging ( J:65577 )

• at 3-4 months of age, female heterozygotes begin to exhibit several features that are consistent with an accelerated aging process, including premature reproductive senescence by about 7 months, skeletal deformity, and late onset of obesity

early reproductive senescence ( J:65577 , J:140008 )

• female heterozygotes display premature reproductive senescence by about 7 months (J:65577)

reproductive system

abnormal female germ cell morphology ( J:140008 )

• at 3 months of age, the oocyte diameters within primordial (stage I) follicles, primary (stage II) follicles, secondary (stage III) follicles and antral follicles of heterozygous ovaries are greater than in wild-type control follicles

• notably, at 7- and 12 months, heterozygous oocyte diameters within all types of follicles are reduced relative to wild-type; however, these differences are significant only within antral follicles of 7-mo-old ovaries and within primordial follicles of 12-mo-old ovaries

absent oocytes ( J:140008 )

• by 12 months of age, the heterozygous ovary is virtually depleted of all oocytes

oocyte degeneration ( J:140008 )

• heterozygous females exhibit accelerated oocyte loss due to atresia and increased follicular cell death in the ovary

• at 7 months of age, heterozygous ovaries have lost 75% of the oocyte pool

absent corpus luteum ( J:140008 )

• by 12 months, the corpus luteum is absent

abnormal granulosa cell morphology ( J:140008 )

• at 3 months, heterozygous mutant ovaries display large numbers of atretic follicles indicating disruption of the cellular layers and pyknotic nuclei, which is typical of atretic granulosa cells

abnormal ovarian follicle number ( J:140008 )

• female heterozygotes a significant decrease in the numbers of growing follicles in their ovary

• by 12 months of age, all heterozygous ovaries are barren while wild-type ovaries retain 30% of values noted at 3 months with active folliculogenesis and hundreds of different types of follicles and corpora lutea

decreased primary ovarian follicle number ( J:140008 )

• female heterozygotes show a 50% reduction in the number of primary follicles

abnormal ovarian folliculogenesis ( J:140008 )

• at 7 months, heterozygous ovaries display pyknotic nuclei and cellular debris in the antrum of some large follicles, many of which appear abnormal

• at 7 months, some follicles contain aberrant or double oocytes while the corpus luteum is sparse

• by 12 months, very few follicles are found, the corpus luteum is absent, and most of the heterozygous ovary consists of fibroid interstitial tissue and cystic follicles

• at 3 months, apoptotic changes in the heterozygous ovary occur predominantly in preantral medium-sized follicles while in wild-type ovaries apoptosis is mostly confined to some granulosa cells of large, antral-size follicles

increased follicle recruitment ( J:140008 )

• by 7 months of age, heterozygous ovaries show an accelerated rate of follicle recruitment from the resting pool as indicated by increased numbers of developing or growing follicles

polyovular ovarian follicle ( J:140008 )

• at 7 months, some follicles contain double oocytes

increased ovary tumor incidence ( J:140008 )

• at >12 months of age, females heterozygotes exhibit ovarian tumors

ovary cyst ( J:70933 , J:140008 )

• by 15 months of age, female heterozygotes exhibit large ovarian cysts, not present in wild-type females (J:70933)

• by 12 months, cysts form the greater part of the ovarian space in some cases (J:140008)

abnormal ovary physiology ( J:140008 )

• female heterozygotes exhibit premature ovarian failure accompanied by degenerative changes, including atresia, apoptosis, and profound loss of oocytes evident by 7 months of age

early reproductive senescence ( J:65577 , J:140008 )

• female heterozygotes display premature reproductive senescence by about 7 months (J:65577)

early vaginal opening ( J:140008 )

• in female heterozygotes the age of pubertal onset occurs ~1.8 days earlier than in wild-type siblings

delayed female fertility ( J:65577 )

• F2 heterozygous females conceive later than wild-type females (at 10-12 weeks versus at 7-8 weeks, respectively)

• the interval between mating and conception gets progressively longer with each pregnancy

long gestation period ( J:140008 )

• in 1-yr-old heterozygous females the interval between establishing the vaginal plug and delivery ranges between 45 and 60 days while age-matched wild-type controls give healthy pups within 24-28 days

abnormal estrous cycle ( J:140008 )

• at 7 months long estrus cycles are interspersed with short ones, and intermittent ovulatory cycles are intermingled with acyclic periods

prolonged diestrus ( J:65577 )

abnormal estrus ( J:65577 )

absent estrous cycle ( J:140008 )

• at 7 months, only 8 of 75 heterozygous females exhibit some cyclicity; the remaining are either acyclic with only leukocytes in the smears or with smears showing persistent vaginal cornification

• cycle frequency drops steadily with age from 4.5 cycles per month at 3 months and 2.5 cycles per month at 7 months and is lost altogether by 1 yr of age

• female heterozygotes show an increased number of cycles with extended cornification at a much earlier age relative to wild-type controls

• the percentage of virgin heterozygotes cycling at 3 months (84%) is reduced to 49% at 7 months and to 0% at 12 months versus 92%, 78%, and 62%, respectively, in virgin wild-type controls

prolonged estrous cycle ( J:65577 , J:140008 )

• heterozygotes display prolonged estrous cycles due to extended diestrus and irregular estrus patterns albeit with normal vaginal cytology (J:65577)

• notably, all heterozygous females show normal signs of estrogen stimulation (full vaginal cornification) during estrus (J:65577)

• at 3 months of age, all heterozygous females show prolonged cycles (~6.2 days) due to extended diestrus versus ~4.9 day cycles in wild-type females (J:140008)

• at 7 months, the mean length of estrous cycle for heterozygous females is ~11.6 days with a range of 4-15 days versus ~5.6 day cycles with a range of 4-7 days in wild-type controls (J:140008)

• at 7 months long estrus cycles are interspersed with short ones, and intermittent ovulatory cycles are intermingled with acyclic periods (J:140008)

female infertility ( J:65577 )

• following ~6-8 births, heterozygous females undergo early reproductive senescence and can no longer conceive, whereas wild-type controls continue to breed for >14 months

reduced female fertility ( J:140008 )

• at 3 months of age, the percentage of mated heterozygous females that deliver litters is 85% relative to 96% in wild-type controls

• at 7 months, the percentage of mated heterozygous females that deliver pups is reduced to 49% versus 83% in wild-type controls

• by 12 months, this percentage is further reduced to 12% while 73% of wild-type controls continue to produce live offspring

decreased litter size ( J:65577 , J:140008 )

• heterozygous females show a >50% reduction in litter size relative to wild-type controls (J:65577)

• heterozygous females mated with wild-type males show a significantly longer time lag between mating and first litter while the number of pups in first litter is reduced by 43% and success at first weaning (pups surviving on P21) is decreased by 25% (J:65577)

• overall breeding performance is more profoundly affected in crosses among heterozygous breeders (J:65577)

• starting at 3 months of age, heterozygous females show a 33% reduction in litter size relative to wild-type littermates (J:140008)

• litter size is further reduced at 7 months (54% less), and by 12 months heterozygous females deliver an average of only 0.5 0.3 offspring that die within 18-48 hrs after birth while 73% of wild-type controls continue to produce viable offspring (J:140008)

homeostasis/metabolism

increased circulating testosterone level ( J:65577 )

• heterozygous females show slightly increased serum testosterone levels relative to wild-type controls

decreased circulating progesterone level ( J:65577 )

• heterozygous females show a 30% reduction in serum progesterone levels relative to wild-type controls

• plasma levels of estradiol also display a decreasing trend but this difference is not significant due to variations among animals

• in the heterozygous uterus, the A form of the progesterone receptor (PR-A) (-64%) is reduced more than PR-B (-44%) relative to wild-type controls

growth/size/body

ovary cyst ( J:70933 , J:140008 )

• by 15 months of age, female heterozygotes exhibit large ovarian cysts, not present in wild-type females (J:70933)

• by 12 months, cysts form the greater part of the ovarian space in some cases (J:140008)

increased body weight ( J:65577 , J:140008 )

• at 3-4 months of age, the body weights of heterozygous females are increased by 9.6% relative to wild-type controls (J:65577)

• although at weaning the average body weight of immature heterozygous females is reduced by 9%, by 7 months their average body weight (~28.3 g) is significantly higher than that of age-matched wild-type females (J:140008)

• by 12 months, the average body weight of female heterozygotes is increased by ~25% relative to wild-type controls (J:140008)

obese ( J:65577 , J:140008 )

• by 10-12 months of age, all heterozygous females become obese (J:65577)

• at 12 months, female heterozygotes are pear-shaped and show clear signs of obesity (J:140008)

skeleton

kyphosis ( J:65577 )

• at 1 year of age, female heterozygotes that show early reproductive senescence also exhibit skeletal abnormalities characterized by a severe stooped posture-kyphosis

behavior/neurological

hunched posture ( J:65577 )

• at 1 year of age, female heterozygotes that show early reproductive senescence also exhibit skeletal abnormalities characterized by a severe stooped posture

endocrine/exocrine glands

absent corpus luteum ( J:140008 )

• by 12 months, the corpus luteum is absent

abnormal granulosa cell morphology ( J:140008 )

• at 3 months, heterozygous mutant ovaries display large numbers of atretic follicles indicating disruption of the cellular layers and pyknotic nuclei, which is typical of atretic granulosa cells

abnormal ovarian follicle number ( J:140008 )

• female heterozygotes a significant decrease in the numbers of growing follicles in their ovary

decreased primary ovarian follicle number ( J:140008 )

• female heterozygotes show a 50% reduction in the number of primary follicles

abnormal ovarian folliculogenesis ( J:140008 )

• at 7 months, heterozygous ovaries display pyknotic nuclei and cellular debris in the antrum of some large follicles, many of which appear abnormal

• at 7 months, some follicles contain aberrant or double oocytes while the corpus luteum is sparse

• by 12 months, very few follicles are found, the corpus luteum is absent, and most of the heterozygous ovary consists of fibroid interstitial tissue and cystic follicles

increased follicle recruitment ( J:140008 )

• by 7 months of age, heterozygous ovaries show an accelerated rate of follicle recruitment from the resting pool as indicated by increased numbers of developing or growing follicles

polyovular ovarian follicle ( J:140008 )

• at 7 months, some follicles contain double oocytes

increased ovary tumor incidence ( J:140008 )

• at >12 months of age, females heterozygotes exhibit ovarian tumors

ovary cyst ( J:70933 , J:140008 )

• by 15 months of age, female heterozygotes exhibit large ovarian cysts, not present in wild-type females (J:70933)

• by 12 months, cysts form the greater part of the ovarian space in some cases (J:140008)

abnormal ovary physiology ( J:140008 )

• female heterozygotes exhibit premature ovarian failure accompanied by degenerative changes, including atresia, apoptosis, and profound loss of oocytes evident by 7 months of age

neoplasm

increased ovary tumor incidence ( J:140008 )

• at >12 months of age, females heterozygotes exhibit ovarian tumors

cellular

abnormal female germ cell morphology ( J:140008 )

absent oocytes ( J:140008 )

• by 12 months of age, the heterozygous ovary is virtually depleted of all oocytes

oocyte degeneration ( J:140008 )

• heterozygous females exhibit accelerated oocyte loss due to atresia and increased follicular cell death in the ovary

• at 7 months of age, heterozygous ovaries have lost 75% of the oocyte pool

increased apoptosis ( J:140008 )

• as early as 3 months of age, TUNEL staining indicates that antral and many preantral ovarian follicles undergo apoptosis

• the percentage of degenerating preantral follicles is significantly higher in heterozygous females relative to wild-type controls (15% versus 4.3%, respectively)

mortality/aging

premature aging ( J:89713 )

• female heterozygotes exhibit premature biological aging

early reproductive senescence ( J:81460 , J:89713 )

• female heterozygotes fail to reproduce after 8-9 months of age ("retired breeders") due to an accelerated loss of ovarian function/oocytes (J:81460)

• female heterozygotes (dubbed "menopausal" mice) exhibit premature reproductive senescence mimicking reproductive failure in postmenopausal women (J:89713)

reproductive system

uterine hemorrhage ( J:81460 )

• aging female heterozygotes sometimes display uterine bleeding as the first sign of uterine pathology

• in areas of hemorrhage, hemosiderin, a golden-yellow to brown granular pigment, is phagocytized by macrophages

abnormal ovary morphology ( J:89713 )

• at 20 months of age, heterozygous ovaries are atrophic and contain no follicles or corpora lutea but only cysts

absent corpus luteum ( J:89713 )

• at 20 months of age

absent ovarian follicles ( J:89713 )

• total exhaustion of ovarian follicles at 20 months of age

ovary atrophy ( J:89713 )

• at 20 months of age

ovary cyst ( J:81460 , J:89713 )

• older virgin heterozygous females bearing a nodular uterine neoplasm in the right uterine horn may also display an ovarian cyst on the contralateral side (J:81460)

• at 20 months of age (J:89713)

early reproductive senescence ( J:81460 , J:89713 )

• female heterozygotes fail to reproduce after 8-9 months of age ("retired breeders") due to an accelerated loss of ovarian function/oocytes (J:81460)

• female heterozygotes (dubbed "menopausal" mice) exhibit premature reproductive senescence mimicking reproductive failure in postmenopausal women (J:89713)

abnormal uterus morphology ( J:81460 )

• at 12 months of age, heterozygous females display an abnormally enlarged uterus with hyperplastic and disorganized luminal epithelium and numerous blood vessels in the uterine stroma suggesting acceleration of angiogenesis

• up to 25% of virgin heterozygous females develop a variable uterine pathology, including cyst-like structures and enlarged lumen, abundant small vessels in the endometrium, adenomyosis, dilated endometrial vessels without thrombosis but associated with hemosiderin containing macrophages, and (in some cases) large uterine masses that resemble organized thrombi composed of red blood cells and fibrin along with increased angiogenesis in the stroma next to the thrombus

• most retired breeders develop larger unilateral uterine masses with varying degrees of thrombi in the outer myometrium of the affected (right) horn, regions of calcification localized in vessels near the myometrium, giant multinucleated cells similar to syncytiotrophoblasts and mononuclear cells resembling cytotrophoblasts, and increased uterine angiogenesis

enlarged endometrial glands ( J:81460 )

• at 12 months of age, endometrial glands are enlarged and the epithelia are hypertrophied

uterus cyst ( J:81460 )

• at 12 months of age, uterine transverse sections reveal the presence of cyst-like structures

increased uterus tumor incidence ( J:81460 )

• by 12 months of age, 23% of virgin heterozygous females and 82% of retired heterozygous female breeders display a large nodular structure (mass) in one uterine horn

• unilateral uterine masses occur predominantly in the right horn (67% of cases), while the left horn remains relatively unaffected

• among different female heterozygotes, the weight of the uterine nodular structure alone ranges from 205 mg to >4000 mg (~8% of the body weight) in extreme cases

enlarged uterus ( J:81460 )

• at 12 months of age

increased uterus weight ( J:81460 )

• by 1 yr of age, heterozygous females with no visible tumors show a 77% increase in uterine weight relative to wild-type females

uterus adenomyosis ( J:81460 )

• some older virgin heterozygous females have endometrial glands and stroma present within the myometrium with no connection to the endometrial cavity

absent estrous cycle ( J:81460 )

• by 12 months of age, most female heterozygotes exhibit highly irregular or absent estrous cycles

abnormal uterine environment ( J:81460 )

• at 8-10 months of age, the % of resorbed pups per pregnancy is significantly increased relative to wild-type controls (12% vs 7% at 10 dpc and 90% vs 18% at 18 dpc, respectively)

• at 10-13 months of age, the % of resorbed pups is further increased, with a fetal resorption rate of 92% at 14 dpc and >92% at 18 dpc vs only ~40% in wild-type controls

• overall, female heterozygotes show a significantly higher rate of pregnancy failure relative to wild-type females

• interestingly, structures resembling fetal tissue persist (or reappear) several months after a failed pregnancy

• pregnancy failure and induction of uterine pathology are associated with an imbalance of progesterone receptor isoforms A and B and an increase in LH receptors in the uterus along with increased angiogenesis, vascular abnormalities, and adenomyosis occuring in the uterine horn bearing the pathological mass

reduced female fertility ( J:81460 )

• as early as 3 months of age, female heterozygotes display reduced fertility relative to wild-type females

decreased litter size ( J:81460 )

• at 3 months of age, female heterozygotes produce ~40% fewer pups than wild-type females (average 5.6 vs 9.8 pups, respectively)

behavior/neurological

increased anxiety-related response ( J:89713 )

• female heterozygotes display a progressive, age-related increase in anxiety in the open field test

• at 20 months of age, female heterozygotes show a 2-fold increase in latency (time required to move from the center of the box to the wall) in an open field, relative to wild-type controls

• no significant differences in latency are observed at 1 month of age, and both heterozygous and wild-type aged mice show increased locomotor activity at 20 months

increased thigmotaxis ( J:89713 )

• at 20 months of age, female heterozygotes show increased thigmotaxis relative to wild-type controls

• however, no significant differences in thigmotaxis are observed between genotypes at 1 month of age

nervous system

astrocytosis ( J:89713 )

• at both 3 and 20 months of age, astroglial cells in the dentate gyrus of female heterozygotes show hypertrophic, swollen pericaria and thick processes relative to wild-type controls

abnormal dentate gyrus morphology ( J:89713 )

• in female heterozygotes, neurons in the dentate gyrus show signs of progressive degenerative changes, hypertrophy and gliosis, with subsequent cell shrinkage and death

neurodegeneration ( J:89713 )

• aging female heterozygotes show degenerative changes in the CNS; the region most affected is the hippocampus

hippocampal neuron degeneration ( J:89713 )

• aging female heterozygotes show altered estrogen receptor expression and significant reductions in choline acetyltransferase enzymatic activity and synapsin immunoreactivity in the hippocampus at 20 months

• early degenerative changes are evident in the hippocampus (dentate gyrus) at 1 month and progress to cell shrinkage and loss at the age of 20 months

homeostasis/metabolism

increased circulating testosterone level ( J:81460 , J:89713 )

• in heterozygous females, plasma testosterone levels are significantly higher than wild-type levels at 12 months, but not at 3 months of age (J:81460)

• female heterozygotes display higher plasma testosterone levels relative to wild-type controls, which become pronounced at 12 and 20 months of age (J:89713)

decreased circulating estradiol level ( J:81460 , J:89713 )

• in heterozygous females, plasma E2 levels are moderately reduced at proestrus at 3 months of age, and significantly reduced by 12 months of age relative to wild-type levels (J:81460)

• at 1 and 3 months of age, female heterozygotes show a moderate reduction in plasma estradiol-17beta (E2) levels relative to wild-type controls; by 7 months of age, plasma E2 levels are virtually undetectable (J:89713)

• notably, expression of nuclear estrogen receptor alpha in the amygdala of aging heterozygotes is increased, whereas expression of estrogen receptor beta in the medial amygdala is markedly reduced, possibly contributing to increased anxiogenic-like behavior (J:89713)

increased circulating follicle stimulating hormone level ( J:81460 )

• in heterozygous females, plasma FSH levels are increased by 77% relative to wild-type levels at 12 months, with no significant differences at 3 months of age

increased circulating luteinizing hormone level ( J:81460 )

• in heterozygous females, plasma LH levels are increased by 33% relative to wild-type levels at 12 months, with no significant differences at 3 months of age

decreased circulating progesterone level ( J:81460 )

• in heterozygous females, plasma progesterone levels are significantly reduced at both 3 and 12 months of age relative to wild-type levels

abnormal thrombosis ( J:81460 )

• many older virgin and retired heterozygous female breeders display dilated uterine vessels with varying degrees of thrombosis in the outer myometrium of the affected uterine horn bearing the pathological mass

abnormal enzyme/coenzyme activity ( J:89713 )

• at 20 months of age, choline acetyltransferase (ChAT) enzymatic activity is reduced by 30% in the hippocampi of female heterozygotes relative to wild-type controls

endocrine/exocrine glands

enlarged endometrial glands ( J:81460 )

• at 12 months of age, endometrial glands are enlarged and the epithelia are hypertrophied

abnormal ovary morphology ( J:89713 )

• at 20 months of age, heterozygous ovaries are atrophic and contain no follicles or corpora lutea but only cysts

absent corpus luteum ( J:89713 )

• at 20 months of age

absent ovarian follicles ( J:89713 )

• total exhaustion of ovarian follicles at 20 months of age

ovary atrophy ( J:89713 )

• at 20 months of age

ovary cyst ( J:81460 , J:89713 )

• older virgin heterozygous females bearing a nodular uterine neoplasm in the right uterine horn may also display an ovarian cyst on the contralateral side (J:81460)

• at 20 months of age (J:89713)

neoplasm

increased uterus tumor incidence ( J:81460 )

• by 12 months of age, 23% of virgin heterozygous females and 82% of retired heterozygous female breeders display a large nodular structure (mass) in one uterine horn

• unilateral uterine masses occur predominantly in the right horn (67% of cases), while the left horn remains relatively unaffected

• among different female heterozygotes, the weight of the uterine nodular structure alone ranges from 205 mg to >4000 mg (~8% of the body weight) in extreme cases

cardiovascular system

uterine hemorrhage ( J:81460 )

• aging female heterozygotes sometimes display uterine bleeding as the first sign of uterine pathology

• in areas of hemorrhage, hemosiderin, a golden-yellow to brown granular pigment, is phagocytized by macrophages

growth/size/body

ovary cyst ( J:81460 , J:89713 )

• older virgin heterozygous females bearing a nodular uterine neoplasm in the right uterine horn may also display an ovarian cyst on the contralateral side (J:81460)

• at 20 months of age (J:89713)

uterus cyst ( J:81460 )

• at 12 months of age, uterine transverse sections reveal the presence of cyst-like structures

cellular

astrocytosis ( J:89713 )

• at both 3 and 20 months of age, astroglial cells in the dentate gyrus of female heterozygotes show hypertrophic, swollen pericaria and thick processes relative to wild-type controls

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

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