Insight into the Ontogeny of GnRH Neurons from Patients Born Without a Nose

Angela Delaney; Rita Volochayev; Brooke Meader; Janice Lee; Konstantinia Almpani; Germaine Y Noukelak; Jennifer Henkind; Laura Chalmers; Jennifer R Law; Kathleen A Williamson; Christina M Jacobsen; Tatiana Pineda Buitrago; Orlando Perez; Chie-Hee Cho; Angela Kaindl; Anita Rauch; Katharina Steindl; Jose Elias Garcia; Bianca E Russell; Rameshwar Prasad; Uttam K Mondal; Hallvard M Reigstad; Scott Clements; Susan Kim; Kaoru Inoue; Gazal Arora; Kathryn B Salnikov; Nicole P DiOrio; Rolando Prada; Yline Capri; Kosuke Morioka; Michiyo Mizota; Roseli M Zechi-Ceide; Nancy M Kokitsu-Nakata; Cristiano Tonello; Siulan Vendramini-Pittoli; Gisele da Silva Dalben; Ravikumar Balasubramanian; Andrew A Dwyer; Stephanie B Seminara; William F Crowley; Lacey Plummer; Janet E Hall; John M Graham; Angela E Lin; Natalie D Shaw

doi:10.1210/clinem/dgaa065

Insight into the Ontogeny of GnRH Neurons from Patients Born Without a Nose

Angela Delaney, Rita Volochayev, Brooke Meader, Janice Lee, Konstantinia Almpani, Germaine Y Noukelak, Jennifer Henkind, Laura Chalmers, Jennifer R Law, Kathleen A Williamson, Christina M Jacobsen, Tatiana Pineda Buitrago, Orlando Perez, Chie-Hee Cho, Angela Kaindl, Anita Rauch, Katharina Steindl, Jose Elias Garcia, Bianca E Russell, Rameshwar PrasadUttam K Mondal, Hallvard M Reigstad, Scott Clements, Susan Kim, Kaoru Inoue, Gazal Arora, Kathryn B Salnikov, Nicole P DiOrio, Rolando Prada, Yline Capri, Kosuke Morioka, Michiyo Mizota, Roseli M Zechi-Ceide, Nancy M Kokitsu-Nakata, Cristiano Tonello, Siulan Vendramini-Pittoli, Gisele da Silva Dalben, Ravikumar Balasubramanian, Andrew A Dwyer, Stephanie B Seminara, William F Crowley, Lacey Plummer, Janet E Hall, John M Graham, Angela E Lin, Natalie D Shaw

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

CONTEXT: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in man led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed.

OBJECTIVE: To determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures.

METHODS: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients.

RESULTS: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet three had spontaneous breast development and two women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to two GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male.

CONCLUSIONS: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with, but may not depend on, olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.

Original language	English
Journal	The Journal of Clinical Endocrinology & Metabolism (JCEM)
Early online date	8 Feb 2020
DOIs	https://doi.org/10.1210/clinem/dgaa065
Publication status	Published - 1 May 2020

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Delaney, A., Volochayev, R., Meader, B., Lee, J., Almpani, K., Noukelak, G. Y., Henkind, J., Chalmers, L., Law, J. R., Williamson, K. A., Jacobsen, C. M., Buitrago, T. P., Perez, O., Cho, C-H., Kaindl, A., Rauch, A., Steindl, K., Garcia, J. E., Russell, B. E., ... Shaw, N. D. (2020). Insight into the Ontogeny of GnRH Neurons from Patients Born Without a Nose. The Journal of Clinical Endocrinology & Metabolism (JCEM). https://doi.org/10.1210/clinem/dgaa065

@article{ae9a0e120eb44867b8a76096a0129dc7,

title = "Insight into the Ontogeny of GnRH Neurons from Patients Born Without a Nose",

abstract = "CONTEXT: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in man led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed.OBJECTIVE: To determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures.METHODS: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients.RESULTS: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet three had spontaneous breast development and two women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to two GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male.CONCLUSIONS: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with, but may not depend on, olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.",

author = "Angela Delaney and Rita Volochayev and Brooke Meader and Janice Lee and Konstantinia Almpani and Noukelak, {Germaine Y} and Jennifer Henkind and Laura Chalmers and Law, {Jennifer R} and Williamson, {Kathleen A} and Jacobsen, {Christina M} and Buitrago, {Tatiana Pineda} and Orlando Perez and Chie-Hee Cho and Angela Kaindl and Anita Rauch and Katharina Steindl and Garcia, {Jose Elias} and Russell, {Bianca E} and Rameshwar Prasad and Mondal, {Uttam K} and Reigstad, {Hallvard M} and Scott Clements and Susan Kim and Kaoru Inoue and Gazal Arora and Salnikov, {Kathryn B} and DiOrio, {Nicole P} and Rolando Prada and Yline Capri and Kosuke Morioka and Michiyo Mizota and Zechi-Ceide, {Roseli M} and Kokitsu-Nakata, {Nancy M} and Cristiano Tonello and Siulan Vendramini-Pittoli and {da Silva Dalben}, Gisele and Ravikumar Balasubramanian and Dwyer, {Andrew A} and Seminara, {Stephanie B} and Crowley, {William F} and Lacey Plummer and Hall, {Janet E} and Graham, {John M} and Lin, {Angela E} and Shaw, {Natalie D}",

note = "Published by Oxford University Press on behalf of the Endocrine Society 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US.",

year = "2020",

month = may,

day = "1",

doi = "10.1210/clinem/dgaa065",

language = "English",

journal = "The Journal of Clinical Endocrinology & Metabolism (JCEM)",

issn = "0021-972X",

publisher = "Oxford University Press",

}

Delaney, A, Volochayev, R, Meader, B, Lee, J, Almpani, K, Noukelak, GY, Henkind, J, Chalmers, L, Law, JR, Williamson, KA, Jacobsen, CM, Buitrago, TP, Perez, O, Cho, C-H, Kaindl, A, Rauch, A, Steindl, K, Garcia, JE, Russell, BE, Prasad, R, Mondal, UK, Reigstad, HM, Clements, S, Kim, S, Inoue, K, Arora, G, Salnikov, KB, DiOrio, NP, Prada, R, Capri, Y, Morioka, K, Mizota, M, Zechi-Ceide, RM, Kokitsu-Nakata, NM, Tonello, C, Vendramini-Pittoli, S, da Silva Dalben, G, Balasubramanian, R, Dwyer, AA, Seminara, SB, Crowley, WF, Plummer, L, Hall, JE, Graham, JM, Lin, AE & Shaw, ND 2020, 'Insight into the Ontogeny of GnRH Neurons from Patients Born Without a Nose', The Journal of Clinical Endocrinology & Metabolism (JCEM). https://doi.org/10.1210/clinem/dgaa065

TY - JOUR

T1 - Insight into the Ontogeny of GnRH Neurons from Patients Born Without a Nose

AU - Delaney, Angela

AU - Volochayev, Rita

AU - Meader, Brooke

AU - Lee, Janice

AU - Almpani, Konstantinia

AU - Noukelak, Germaine Y

AU - Henkind, Jennifer

AU - Chalmers, Laura

AU - Law, Jennifer R

AU - Williamson, Kathleen A

AU - Jacobsen, Christina M

AU - Buitrago, Tatiana Pineda

AU - Perez, Orlando

AU - Cho, Chie-Hee

AU - Kaindl, Angela

AU - Rauch, Anita

AU - Steindl, Katharina

AU - Garcia, Jose Elias

AU - Russell, Bianca E

AU - Prasad, Rameshwar

AU - Mondal, Uttam K

AU - Reigstad, Hallvard M

AU - Clements, Scott

AU - Kim, Susan

AU - Inoue, Kaoru

AU - Arora, Gazal

AU - Salnikov, Kathryn B

AU - DiOrio, Nicole P

AU - Prada, Rolando

AU - Capri, Yline

AU - Morioka, Kosuke

AU - Mizota, Michiyo

AU - Zechi-Ceide, Roseli M

AU - Kokitsu-Nakata, Nancy M

AU - Tonello, Cristiano

AU - Vendramini-Pittoli, Siulan

AU - da Silva Dalben, Gisele

AU - Balasubramanian, Ravikumar

AU - Dwyer, Andrew A

AU - Seminara, Stephanie B

AU - Crowley, William F

AU - Plummer, Lacey

AU - Hall, Janet E

AU - Graham, John M

AU - Lin, Angela E

AU - Shaw, Natalie D

N1 - Published by Oxford University Press on behalf of the Endocrine Society 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US.

PY - 2020/5/1

Y1 - 2020/5/1

N2 - CONTEXT: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in man led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed.OBJECTIVE: To determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures.METHODS: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients.RESULTS: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet three had spontaneous breast development and two women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to two GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male.CONCLUSIONS: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with, but may not depend on, olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.

AB - CONTEXT: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in man led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed.OBJECTIVE: To determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures.METHODS: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients.RESULTS: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet three had spontaneous breast development and two women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to two GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male.CONCLUSIONS: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with, but may not depend on, olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.

U2 - 10.1210/clinem/dgaa065

DO - 10.1210/clinem/dgaa065

M3 - Article

C2 - 32034419

SN - 0021-972X

JO - The Journal of Clinical Endocrinology & Metabolism (JCEM)

JF - The Journal of Clinical Endocrinology & Metabolism (JCEM)

ER -

Insight into the Ontogeny of GnRH Neurons from Patients Born Without a Nose

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