The Genetic Backdrop of Hypogonadotropic Hypogonadism

The pituitary is an organ of dual provenance: the anterior lobe is epithelial in origin, whereas the posterior lobe derives from the neural ectoderm. The pituitary gland is a pivotal element of the axis regulating reproductive function in mammals. It collects signals from the hypothalamus, and by secreting gonadotropins (FSH and LH) it stimulates the ovary into cyclic activity resulting in a menstrual cycle and in ovulation. Pituitary organogenesis is comprised of three main stages controlled by different signaling molecules: first, the initiation of pituitary organogenesis and subsequent formation of Rathke’s pouch; second, the migration of Rathke’s pouch cells and their proliferation; and third, lineage determination and cellular differentiation. Any disruption of this sequence, e.g., gene mutation, can lead to numerous developmental disorders. Gene mutations contributing to disordered pituitary development can themselves be classified: mutations affecting transcriptional determinants of pituitary development, mutations related to gonadotropin deficiency, mutations concerning the beta subunit of FSH and LH, and mutations in the DAX-1 gene as a cause of adrenal hypoplasia and disturbed responsiveness of the pituitary to GnRH. All these mutations lead to disruption in the hypothalamic–pituitary–ovarian axis and contribute to the development of primary amenorrhea.

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SAT-291 SIX3 Is Essential for Hypothalamic and Pituitary Development

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.159 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Hironori Bando ◽

Michelle L Brinkmeier ◽

Frederic Castinetti ◽

Peter Gergics ◽

Amanda H Mortensen ◽

...

Keyword(s):

Bmp Signaling ◽

Pituitary Hormone ◽

Homeodomain Protein ◽

Loss Of Function ◽

Shh Signaling ◽

Rathke’S Pouch ◽

Pituitary Development ◽

Rathke's Pouch ◽

Oral Ectoderm ◽

Congenital Hypopituitarism

Abstract The genetic basis for congenital hypopituitarism and related disorders is beginning to emerge, and over causal 30 genes have been identified, including six in the SHH signaling pathway. Mutations in some of these genes can also cause holoprosencephaly (HPE) or septo-optic dysplasia. SIX3 is a homeodomain protein expressed in the developing brain, pituitary gland, and eye. It activates SHH signaling and represses BMP signaling. Heterozygous mutations in SIX3 cause variable HPE in humans and mice. We identified a rare, heterozygous variant in SIX3 in two children with neonatal GH and TSH deficiency and stalk interruption, p.P74R. Using transient transfection in 3T3 cells, we demonstrated that the variant reduced the ability of SIX3 to transactivate the SHH enhancer and promoter of FOXG1, suggesting that the variant could be deleterious. To understand the role of SIX3 in hypothalamic and pituitary development we used Nkx2.1-cre and Prop1-cre to delete Six3 in mice. The Nkx2.1-cre, Six3flox/flox embryos had no evidence of infundibulum evagination or expression of Fgf10 or Tcf7l2 at e11.5. The oral ectoderm invaginated in mutants, but no definitive Rathke’s pouch formed. There was no evidence of Lhx3 expression and only trace amounts of Pitx1, indicating that pituitary induction failed due to the lack of Six3 in the developing hypothalamus. Similarly, disruption of Six3 expression in Rathke’s pouch using Prop1-cre ablated pituitary development. Together, these data reveal essential roles of Six3 in both the neural and oral ectoderm for hypothalamic and pituitary development, respectively. Heterozygous loss of function variants in SIX3 could be a contributor to multiple pituitary hormone deficiencies in children, especially if there are associated craniofacial abnormalities.

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Reduced expression of the LIM-homeobox gene Lhx3 impairs growth and differentiation of Rathke’s pouch and increases cell apoptosis during mouse pituitary development

Mechanisms of Development ◽

10.1016/j.mod.2006.06.005 ◽

2006 ◽

Vol 123 (8) ◽

pp. 605-613 ◽

Cited By ~ 34

Author(s):

Yangu Zhao ◽

Donna Chelle Morales ◽

Edit Hermesz ◽

Woon-Kyu Lee ◽

Samuel L. Pfaff ◽

...

Keyword(s):

Cell Apoptosis ◽

Homeobox Gene ◽

Rathke’S Pouch ◽

Pituitary Development ◽

Rathke's Pouch ◽

Mouse Pituitary

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Pitx2is required at multiple stages of pituitary organogenesis: pituitary primordium formation and cell specification

Development ◽

10.1242/dev.129.2.329 ◽

2002 ◽

Vol 129 (2) ◽

pp. 329-337 ◽

Cited By ~ 5

Author(s):

Hoonkyo Suh ◽

Philip J. Gage ◽

Jacques Drouin ◽

Sally A. Camper

Keyword(s):

Transcription Factors ◽

Homeobox Gene ◽

Threshold Level ◽

Cell Types ◽

Allelic Series ◽

Rieger Syndrome ◽

Rathke’S Pouch ◽

Pituitary Development ◽

Rathke's Pouch ◽

Multiple Stages

Analysis of an allelic series in mice revealed that the Pitx2 homeobox gene is required at multiple stages of pituitary development. It is necessary for initiating expansion of Rathke’s pouch and maintaining expression of the fetal-specific transcription factors Hesx1 and Prop1. At later stages Pitx2 is necessary for specification and expansion of the gonadotropes and Pit1 lineage within the ventral and caudomedial anterior pituitary. Mechanistically, this is due to the dependence of several critical lineage-specific transcription factors, Pit1, Gata2, Egr1 and Sf1, on a threshold level of PITX2. The related Pitx1 gene has a role in hormone gene transcription, and it is important late in ontogeny for the final expansion of the differentiated cell types. Pitx1 and Pitx2 have overlapping functions in the expansion of Rathke’s pouch, revealing the sensitivity of pituitary organogenesis to the dosage of the PITX family. The model developed for PITX gene function in pituitary development provides a better understanding of the etiology of Rieger syndrome and may extend to other PITX-sensitive developmental processes.

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SIX3 Variant Causes Pituitary Stalk Interruption Syndrome and Combined Pituitary Hormone Deficiency

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1079 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A530-A530

Author(s):

Hironori Bando ◽

Michelle Brinkmeier ◽

Peter Gergics ◽

Qing Fang ◽

Amanda Helen Mortensen ◽

...

Keyword(s):

Pituitary Gland ◽

Genetic Interaction ◽

Pituitary Stalk ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Beta Catenin ◽

Loss Of Function ◽

Rathke’S Pouch ◽

Pituitary Development ◽

Rathke's Pouch

Abstract The genetic basis for congenital hypopituitarism and related disorders is beginning to emerge, and over 30 causal genes have been identified. Mutations in some of these genes can also cause holoprosencephaly (HPE) or septo-optic dysplasia. SIX3 is a homeodomain protein expressed in the developing brain, pituitary gland, and eye. Heterozygous mutations in SIX3 cause variable HPE in humans and mice. We identified two children with neonatal GH and TSH deficiency and stalk interruption who were doubly heterozygous for rare, likely deleterious variants in SIX3 and POU1F1. Functional studies demonstrated that both variants are disruptive. We used Six3 and Pou1f1 loss of function mice to assess the genetic interaction between Six3 and Pou1f1. Six3 heterozygotes have variable pituitary gland dysmorphology, while Pou1f1 heterozygotes are normal. A significant portion of the Six3+/-; Pou1f1+/dw doubly heterozygous mice have a more pronounced pituitary phenotype than Six3+/-, supporting the possibility of digenic pituitary disease. To understand the role of SIX3 in pituitary and hypothalamic development, we used Prop1-cre and Nkx2.1-cre to delete Six3. Disruption of Six3 expression in Rathke’s pouch caused poor activation of Lhx3 expression and arrested anterior pituitary development. The Nkx2.1-cre, Six3flox/flox embryos had no evidence of infundibulum evagination and failed to induce FGF and BMP signaling, which normally drive expansion of Rathke’s pouch. By E11.5 cells in Rathke’s pouch underwent apoptosis. The Nkx2.1-cre, Six3flox/flox embryos failed to activate expression of Lhx2 and Tbx3 in the neural ectoderm. These embryos had elevated CCND1, MYCN, and Axin2 expression in the area of the presumptive infundibulum. This indicates that SIX3 is necessary to repress cell proliferation and Wnt/beta-catenin signals to promote formation of the pituitary stalk. Thus, Six3 has essential roles in both the neural and oral ectoderm for hypothalamic and pituitary development, respectively. Heterozygous loss of function variants in SIX3 could be a contributor to multiple pituitary hormone deficiencies in children, especially if there are associated craniofacial abnormalities or PSIS.

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Hydrocephalus and hypothalamic involvement at the time of initial diagnosis – Impact on long-term prognosis in 177 pediatric patients with craniopharyngioma and cysts of Rathke's pouch recruited in HIT Endo

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0035-1547671 ◽

2015 ◽

Vol 122 (03) ◽

Author(s):

AMM Daubenbüchel ◽

A Hoffmann ◽

M Warmuth-Metz ◽

U Gebhardt ◽

AS Sterkenburg ◽

...

Keyword(s):

Pediatric Patients ◽

Initial Diagnosis ◽

Rathke’S Pouch ◽

Rathke's Pouch ◽

Long Term Prognosis

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Accumulation of secretory granules in pituitary clonal cells derived from the epithelium of Rathke's pouch

Cell and Tissue Research ◽

10.1007/bf00219654 ◽

1978 ◽

Vol 186 (1) ◽

Cited By ~ 5

Author(s):

Masataka Shiino ◽

Hiroshi Ishikawa ◽

EdwardG. Rennels

Keyword(s):

Secretory Granules ◽

Rathke’S Pouch ◽

Rathke's Pouch

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Enhancement of the Canonical Wnt Pathway in Rathke's Pouch Results in Pituitary Tumours Reminiscent of Human Adamantinomatous Craniopharyngioma.

10.1210/endo-meetings.2010.part3.or2.or38-3 ◽

2010 ◽

pp. OR38-3-OR38-3

Author(s):

Carles Gaston-Massuet ◽

Cynthia L Andoniadou ◽

Massimo Signore ◽

Sajutha Jayakody ◽

Nicoletta Charolidi ◽

...

Keyword(s):

Wnt Pathway ◽

Pituitary Tumours ◽

Rathke’S Pouch ◽

Rathke's Pouch ◽

Canonical Wnt Pathway ◽

Adamantinomatous Craniopharyngioma ◽

Canonical Wnt

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A Rare Case of Coexistence of Pituitary Stalk Interruption Syndrome and Mayer-Rokitansky-Küster-Hauser Syndrome

10.21203/rs.3.rs-91618/v1 ◽

2020 ◽

Author(s):

Wanlu Ma ◽

Xi Wang ◽

jiangfeng mao ◽

Min Nie ◽

Xueyan Wu

Keyword(s):

Computed Tomography ◽

Differential Diagnosis ◽

Rare Case ◽

Hypogonadotropic Hypogonadism ◽

Pituitary Stalk ◽

Primary Amenorrhea ◽

Case Presentation ◽

Mrkh Syndrome ◽

Breech Delivery ◽

Prepubertal Girls

Abstract Background Pituitary stalk interruption syndrome (PSIS) is a rare congenital pituitary anatomical disorder. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital absence of the uterus, cervix, and part of the vagina in phenotypically normal 46, XX females. Case presentation A young woman was initially diagnosed as MRKH syndrome based on primary amenorrhea, 46, XX karyotype, and absence of uterus or vagina. Further investigation revealed breech delivery, short stature, hypogonadotropic hypogonadism, interrupted pituitary stalk on pituitary MRI, which led to the diagnosis of PSIS. After a 12-month treatment with estradiol, no signs of uterus or vagina were found on pelvic computed tomography.Conclusions We highlight the importance of considering PSIS in the differential diagnosis of suspected MRKH syndrome in prepubertal girls or girls with delayed or absent puberty, when no uterus is visualized on imaging.

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