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Applied Endocrinology
• Fetal growth retardation (FGR) caused by
– Ovarian development
– Hippocampal development
– Penile and urethral tissue development
• Freemartinism
FGR- ovarian development
• Follicular pool is established in utero
• Placental estrogen levels increase with
• Estrogen regulates fetal ovarian follicle
Follicle development
• Low serum estradiol levels
– Can lead to a 50% decrease in growing follicles
– Majority of the remaining follicles developing
contain unhealthy oocytes
• Lead to sub-fertility
• Non-steroidal
aromatase inhibitor
– Aromatase converts
androstenedione to
• Leads to decreased
levels of serum
Puberty and Postmenarche
• Decreased serum estrogen levels during
– Delayed on set of puberty
– Increased postmenarche cycle length
• Letrozole treated animals showed a cycle that lasted
six days longer
Hippocampal Development
• Hippocampus
develops from the
• Important for
learning and memory
• Programmed for normal development and
function by estrogen
• Estrogen regulates development of synapse
formation, long-term potential of the
hippocampus, and a neuroprotective effect
on stress
Estrogen affects on Hippocampal
• Disruption in hippocampal estrogen synthesis
– Loss of spine synapse in hippocampus
• Two main receptors: alpha and beta
– Estrogen receptor alpha
• Responsible for mediating estrogen through the direction of
homodimer binding to estrogen
– Homodimer binding is the binding of substrates to transcription
factors to mediate the translation of DNA
Fetal growth retardation
• FGR causes estrogen levels in tissues of the
hippocampal to decrease
Male vs. Female development
• FGR decreases the
• No affect
programming of
estrogen and estrogen
receptors in the
• Cause the hippocampal
to not develop fully
Penile and Urethral development
• Exposure to synthetic
estrogen during
– Disruption in the
formation of the
urethral seam
• Urethral seam does not
fully close
• Hypospadias
– Leads to difficult urination,
ejaculation and sub-fertility
• Urethral seam closure
– Caused by apoptosis
– Synthetic estrogen causes:
• Apoptosis to be eliminated
• Suppression of growth of the
genital tubercle
• Exposure of high estrogen
– Only 36 hours
• Affects development of penile and urethral tissue
• Co-gestation of male and female
– Male fetus develops sooner than female
• Day 40- gonads begin to differentiate into testis
– Testis (Sertoli cells) secrete anti-Müllerian hormone
• Day 80- Leydig cells secrete testosterone
– Stimulates the Wolffian duct system to develop into the
epididymis and the vas deferens
– Female fetus develops later in gestation
• Day 60- uterine part of Müllerian duct starts to enlarge
– Develops into the oviducts, uterus, cervix, and anterior vagina
• Day 70- meiosis begins in the ovaries
• Day 79- the Wolffian duct regresses
• Common circulation of blood between male
and female conceptuses
• Anti-Müllerian hormone and testosterone
present first
– Exert effects on the female conceptus
• Short, blind ending vagina
• Posterior vagina normal because of development from
perineal region
Freemartins and placental types
• Cotyledonary placenta
– Cattle
• Shared blood supply
• Diffuse
– Pig
• Avascularized tips
Clinical examination
• Normal and freemartin animals can be differentiated
on the basis of the length of the vagina and presence
or absence of a cervix
– Normal vaginal length
• Adult- 30cm
• Calves- 13-15cm
– Freemartin
• Adult- 8-10cm
• Calves- 5-6cm
• Use a blunt probe that is
well lubricated
• Insert at 45° angle below
the horizontal for
approximately two
inches and then angle
downward to avoid
catching the hymen
If time…
• Distal hypospadias repair animation
Pepe, Gerald J., Terrie J. Lynch, and Eugene D. Albrecht. Regulation of Baboon Fetal Ovarian
Development by Placental Estrogen: Onset of Puberty is Delayed in Offspring Deprived of
Estrogen In Utero. Journal of Biology of Reproduction. 2013. 89(6); 123, 1-8. DOI:
Numpang, Ben. Xingrao Ke, Xing Yu, Christopher Callaway, Robert McKnight, Lisa Joss-Moore, and
Robert Lane. Fetal growth restriction alters hippocampal 17-beta estradiol estrogen receptor
alpha levels in the newborn male rat. Journal of Systems Biology in Reproductive Medicine. 2013.
59; 184-190. DOI: 10.3109/19396368.2013.786767
Ma, Li-Min, Zhong Wang, Hao Wang, Run-Sheng Li, Joan Zhou, Ben-Chun Liu, and Laurence S.
Baskin. Estrogen Effects on Fetal Penile and Urethral Development in Organotypic Mouse Genital
Tubercle Culture. Journal of Urology. 2009. 182. 2511-2517. DOI: 10.1016/j.juro.2009.07.008
Long, Susan E. Development and diagnosis of freemartinism in cattle. In Practice. Sept. 1990. 208210.