Article

PDF
Access to the PDF text
Service d'aide à la décision clinique
Advertising


Free Article !

Annales d'Endocrinologie
Volume 71, n° 3
pages 158-162 (mai 2010)
Doi : 10.1016/j.ando.2010.02.024
Congenital hypogonadotropic hypogonadism in females: Clinical spectrum, evaluation and genetics
Hypogonadisme hypogonadotrope chez la femme : clinique, exploration et diagnostic génétique
 

H. Bry-Gauillard a, b, S. Trabado c, d, J. Bouligand c, d, J. Sarfati a, c, B. Francou c, d, S. Salenave a, P. Chanson a, c, S. Brailly-Tabard c, d, A. Guiochon-Mantel c, d, J. Young a, , c
a Service d’endocrinologie et des maladies de la reproduction, centre hospitalier universitaire de Bicêtre, Assistance Publique–Hôpitaux de Paris, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre, France 
b Service de gynécologie, obstétrique et procréation médicale assistée, hôpital intercommunal de Créteil, Créteil, France 
c Inserm U693, faculté de médecine Paris Sud, université Paris-Sud 11, Paris, France 
d Service de génétique moléculaire, pharmacogénétique et hormonologie, centre hospitalier universitaire de Bicêtre, Assistance publique–Hôpitaux de Paris, 94275 Le Kremlin-Bicêtre, France 

Corresponding author.
Résumé

Les hypogonadismes hypogonadotrophiques congénitaux (HHC) sont une cause bien connue de défaillance du développement pubertaire chez la femme. Chez la grande majorité des patientes, le tableau clinique résulte de la sécrétion insuffisante et concomitante des deux gonadotrophines hypophysaires LH et FSH qui empêchent un fonctionnement normal ovarien endocrine et exocrine cyclique après l’âge d’activation pubertaire de l’axe gonadotrope. Dans des cas exceptionnels mais intéressants, elles peuvent découler d’un déficit électif d’une des gonadotrophines FSH ou LH par anomalie génétique de leur sous-unité ß spécifique. La prévalence de l’HHC, estimée à partir de séries hospitalières est considérée comme deux à cinq fois moins importante chez les femmes par rapport aux hommes atteints de ces maladies. Cette fréquence est probablement sous-estimée du fait d’un diagnostic insuffisant des formes avec développement pubertaire partiel. Les formes isolées ou apparemment isolées (i.e., syndrome de Kallmann avec anosmie ou hyposmie non exprimée spontanément par les patients) de ces maladies sont découvertes le plus souvent pendant l’adolescence ou à l’âge adulte devant un développement pubertaire absent, incomplet ou apparemment complet mais avec quasi constamment une aménorrhée primaire. Dans une minorité de cas et surtout dans les formes familiales des causes génétiques à transmission autosomique ont été retrouvées. Il s’agit dans ces cas de mutations de gènes affectant le fonctionnement de la cascade de signalisation hypothalamo-hypophysaire impliquée dans la sécrétion normale de LH et FSH (mutations de GnRHR , GnRH1 , KISS1R/GPR54 , TAC3 , TACR3 ) et qui sont toujours associées à des déficits gonadotropes congénitaux isolés, avec olfaction normale et non syndromiques. Des cas de mutations de FGFR1 , plus rarement de son ligand FGF8 , ou de PROKR2 ou son ligand PROK2 ont été mis en évidence chez des femmes atteintes de syndrome de Kallmann ou de son variant hyposmique ou normosmique. Dans les causes syndromiques complexes (mutations de CHD7 , anomalies de la leptine et de son récepteur, syndrome de Prader-Willi, etc.) le diagnostic de la cause de l’HHC est actuellement le plus souvent suspecté ou posé avant l’âge de la puberté du fait des signes cliniques associés mais dans quelques rares cas des causes syndromiques peu symptomatiques peuvent initialement se présenter à l’adolescence comme des HHC isolés non syndromiques ou des syndromes de Kallmann.

The full text of this article is available in PDF format.
Abstract

Congenital hypogonadotropic hypogonadisms (CHH) are a well-known cause of pubertal development failure in women. In a majority of patients, the clinical spectrum results from an insufficient and concomitant secretion of both pituitary gonadotropins LH and FSH that impedes a normal endocrine and exocrine cyclical ovary functioning after the age of pubertal activation of gonadotropic axis. In exceptional but interesting cases, they can result from an elective deficit of one of the gonadotropins follicle-stimulating hormone (FSH) or luteinizing hormone (LH) by genetic anomaly of their specific ß sub-unit. CHH prevalence, estimated from teaching hospital series, is considered to be two to five fold less important in women compared to men bearing the disease. This frequency is probably under-estimated in reason of under-diagnosis of forms with partial pubertal development. Isolated or apparently isolated forms (i.e., Kallmann syndrome with anosmia or hyposmia not spontaneously expressed by the patients) of these diseases are most of the time discovered during adolescence or in adulthood in reason of lacking, incomplete or even apparently complete pubertal development, but with almost constant primary amenorrhea. In a minority of cases and mainly in familial forms, genetic autosomal causes have been found. These cases are related to mutations of genes impinging the functioning of the pituitary-hypothalamic pathways involved in the normal secretion of LH and FSH (mutations of GnRHR , GnRH1 , KISS1R/GPR54 , TAC3 , TACR3 ), which are always associated to isolated non syndromic CHH without anosmia. Some cases of mutations of FGFR1 , and more rarely of its ligand FGF8, or of PROKR2 or its ligand PROK2 have been shown in women suffering from Kallmann syndrome or its hyposmic or normosmic variant. In complex syndromic causes (mutations of CHD7 , leptin and leptin receptor anomalies, Prader-Willi syndrome, etc.), diagnosis of the CHH cause is most often suspected or set down before the age of puberty in reason of the associated clinical signs, but some rare cases of paucisymptomatic syndromic causes can initially be revealed during adolescence, like isolated non syndromic CHH or Kallmann syndrome.

The full text of this article is available in PDF format.

Mots clés : Hypogonadisme hypogonadotrope congénital de la femme, Anosmie, Syndrome de Kallmann, Aménorrhée, GnRH, Infertilité

Keywords : Congenital hypogonadotropic hypogonadism in women, Anosmia, Kallmann syndrome, Amenorrhea, GnRH, Gonadotropins


Congenital hypogonadotropic hypogonadism (CHH) results from abnormal gonadotropin secretion and is characterized by a complete or partial lack of pubertal development that is caused mainly by defective GnRH production or release by the hypothalamus, or by a primary gonadotropic cell dysfunction in the pituitary. The prevalence of CHH, evaluated from 1/10,000 to 1/4000 in males, was reported to be between two and five times less frequent in females [1, 2]. These values mainly established by specialized teams belonging to teaching hospitals (Fig. 1) are probably underestimated compared to the real frequency of CHH in the general population of women as a consequence of recruitment biases. CHH is revealed in the majority of female teenagers and women by primary amenorrhea [1, 2, 3, 4, 5, 6]. The classical hormonal signature of CHH is a low level of circulating sex steroids, together with low or “normal” levels of FSH and LH [1, 2, 3, 4, 5, 6].



Fig. 1


Fig. 1. 

Distribution by sex of patients evaluated for congenital hypogonadotropic hypogonadism at the Endocrinology and Reproduction Department, Bicêtre Teaching Hospital. (update :march 2010)

Zoom

Clinical presentation

In women, CHH is revealed in by primary amenorrhea in more than 90% of cases [3]. Breast development is highly variable but it is absent in a minority of cases (Fig. 2). Indeed, it is often present and sometimes almost normal. Similarly, pubic hair may be absent (Fig. 2), sparse or even normal. These partial forms, in majority not referred to hospital contribute to explaining the underestimated prevalence of this condition in women [1, 3]. In a very mild form, CHH can be restricted to isolated chronic anovulation, whereas estradiol secretion is adequate for endometrial development and therefore associated with the existence of a single menstruation (primosecondary amenorrhea) or even chronic oligomenorrhea or a positive progestin withdrawal test [3]. These attenuated forms have also been described in women having conceived spontaneously [7].



Fig. 2


Fig. 2. 

Complete congenital hypogonadotropic hypogonadism in a 22-year-old woman referred for primary amenorrhea.

Zoom

One challenge in women with sporadic CHH, normal olfaction and hypothalamopituitary MRI and no identified mutation is the differential diagnosis of functional hypothalamic amenorrhea [1, 8, 9]. In women referred for primary amenorrhea and with an hormonal profile suggesting HH but without anosmia or hyposmia or identified genetic anomalies, the diagnosis of CHH must therefore only be considered with care, after ruling out underweight, eating disorders, excessive physical activity, and chronic underlying conditions (Fig. 3) [1, 8, 9]. When body weight or BMI are at the lower limit of normal, body fat measurement can also be useful to screen for functional hypothalamic amenorrhea in this context.



Fig. 3


Fig. 3. 

Steps to overcome before achieving the diagnosis of congenital hypogonadotropic hypogonadism (CHH) in women or female teenagers referred for primary amenorrhea.

Zoom

Finally, the presence of non-reproductive non-olfactory additional disorders, including mirror movements, palate anomalies, renal agenesis (ultrasonography), hearing impairment (audiometric testing), and tooth agenesis, should be carefully searched in these female patients and, whenever possible, their first-degree relatives, because such anomalies can direct the clinicians and geneticist towards particular genetic forms of the disease [10] (Kallmann syndrome or more complex syndromic causes) in which genetic counseling is mandatory.

Evaluation

Serum estradiol concentrations are often low in women with CHH [1, 2, 3, 4, 5, 6], sometimes below the detection limit. They seem to correlate with breast development: indeed, in the absence of breast development, circulating estradiol concentrations are undetectable while estradiol is detectable with a sensitive assay when breast development exceeds stage B2. A similar relationship exists between pubertal development and pituitary gonadotropin concentrations: the latter are often very low or undetectable in the absence of breast development, while in patients with stage B3 or B4 breast development, they can reach values close to those observed in the early follicular phase of women with normal cycles (Fig. 3). As in males with CHH, the GnRH test have a poor diagnosis value to make a positive diagnosis in females and serves more to confirm the severity of congenital gonadotropin deficiency [11], which in fact is often already clinically perceptible (reflected by the degree of breast development). Thus, the GnRH test provides no extra diagnostic information relative to baseline gonadotropin levels evaluated with modern assays [1]. In addition, it cannot show whether the gonadotropin deficiency is hypothalamic or pituitary in origin: for instance, the results of GnRH test can be negative in profound hypothalamic gonadodropin deficiency and positive in partial pituitary deficiency [1, 2, 3, 4, 5, 6, 11].

Before making a firm diagnosis of isolated congenital gonadotropin deficiency, all antepituitary functions must be investigated in order not to miss hyperprolactinemia, global anterior pituitary insufficiency, or an associated endocrine disorder that may be part of a syndromic form of CHH (Fig. 3).

On the same way, in the absence of anosmia or other associated signs suggesting a syndromic cause, primary juvenile hemochromatosis may mimic CHH and be a real differential diagnosis [12]. It is therefore useful to rule out iron overload, given the therapeutic implications in this disorder. Primary juvenile hemochromatosis can be ruled out by measuring serum iron and the transferrin saturation coefficient.

Imaging

Pelvic sonography is useful for determining the size of the uterus [13, 14, 15], which reflects estrogen impregnation, as well as endometrial thickness, ovary size and the number and size of ovarian follicles [13, 14, 15], that may correlate with the severity of gonadotropin deficiency [3].

MRI of the brain and olfactory bulbs is useful in CHH. Although the findings are nearly always normal in isolated normosmic CHH, MRI can rule out an expansive, infiltrative or malformative disorder of the hypothalamopituitary region. MRI can also be used to analyze the olfactory bulbs and furrows in a search for signs of Kallmann syndrome.

Genetics

Identification of genetic abnormalities related to CHH over the last 2 decades has provided important insights into the pathways involved in the development, maturation and function of the reproductive axis. In women, mutations of FGFR1 , PROK2 , PROKR2 and FGF8 have been found specifically in Kallmann syndrome, a disorder in which CHH is related to abnormal GnRH neuron ontogenesis and is associated with anosmia or hyposmia [6, 10, 11, 12, 13, 14, 15, 16, 17, 18] (Fig. 4).



Fig. 4


Fig. 4. 

Molecular studies proposed at the Endocrinology and Reproduction Department, Bicêtre Teaching Hospital to females with CHH categorized on the basis of sense of smell.

Zoom

In fact, in females as in males, the CHH phenotype is usually tightly linked to an isolated deficiency of gonadotrophin secretion. These patients, who have no clinical abnormalities, associated signs or hormone deficiencies independent of the deficiency in gonadotrophin and sex steroids, have isolated CHH [1]. Such cases are occasionally due to genetic alterations affecting GnRH secretion: mutations in GNRH1 [5], GPR54/KISS1R [19, 20] and TAC3 and TACR3 [21, 22, 23] or the GnRH sensitivity of gonadotropic cells: GNRHR [1, 4, 24, 25] (Fig. 4).

Since more than 20 years, we have learned a great deal from a number of genotype-phenotype published studies: so, we know now the clinical features of patients with GnRHR gene mutations where both genders are highly variable, even in the same kindred [1]. On the same way, whatever the mutations, it has been clearly established that the spectrum of the reproductive phenotype in women with CHH, is much broader than originally anticipated (Fig. 5). There is no doubt that, these findings have changed our old oversimplified view of the disease.



Fig. 5


Fig. 5. 

Genotype–phenotype relationship in women with normosmic non syndromic CHH caused by GnRH receptor loss of function mutations. Adapted from [1].

Zoom

Finally, we must be aware that a minority of female patients with Kallmann syndrome or a syndromic form of CHH may also initially appear to have isolated CHH. Close clinical, familial and genetic studies can correct the diagnosis, which is particularly important for genetic counselling [1, 26].

Conflicts of interest

Aucun.

References

Brioude F, Bouligand J, Trabado S, Salenave S, Kamenicki P, Brailly-Tabard S, et al. Non syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype/phenotype relationships Eur J Endocrinol. 2010 Mar 5. [Epub ahead of print].
Seminara S.B., Hayes F.J., Crowley W.F. Gonadotropin-releasing hormone deficiency in the human (idiopathic hypogonadotropic hypogonadism and Kallmann’s syndrome): pathophysiological and genetic considerations Endocr Rev 1998 ;  19 : 521-539 [cross-ref]
Young J, Vincent D, Bachelot A, Kottler ML, Dode C, Plotton I, et al. Congenital hypogonadotrophic hypogonadism in women: Clinical presentation, hormonal evaluation; Ovarian morphological and genetic studies in a series of 104 patients. A multicenter survey. In xxiii Congrès de la Société Française d’Endocrinologie. Montpellier, 2006.
de Roux N., Young J., Misrahi M., Genet R., Chanson P., Schaison G., and al. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor N Engl J Med 1997 ;  337 : 1597-1602 [cross-ref]
Bouligand J., Ghervan C., Tello J.A., Brailly-Tabard S., Salenave S., Chanson P., and al. Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation N Engl J Med 2009 ;  360 : 2742-2748 [cross-ref]
Sarfati J., Guiochon-Mantel A., Rondard P., Arnulf I., Garcia-Piñero A., Wolczynski S., and al. A comparative phenotypic study of kallmann syndrome patients carrying monoallelic and biallelic mutations in the prokineticin 2 or prokineticin receptor 2 genes J Clin Endocrinol Metab 2010 ;  95 (2) : 659-669 [cross-ref]
Dewailly D., Boucher A., Decanter C., Lagarde J.P., Counis R., Kottler M.L. Spontaneous pregnancy in a patient who was homozygous for the Q106R mutation in the gonadotropin-releasing hormone receptor gene Fertil Steril 2002 ;  77 (6) : 1288-1291 [cross-ref]
Couzinet B., Young J., Brailly S., Le Bouc Y., Chanson P., Schaison G. Functional hypothalamic amenorrhoea: a partial and reversible gonadotrophin deficiency of nutritional origin Clin Endocrinol (Oxf) 1999 ;  50 : 229-235 [cross-ref]
Perkins R.B., Hall J.E., Martin K.A. Aetiology, previous menstrual function and patterns of neuro-endocrine disturbance as prognostic indicators in hypothalamic amenorrhoea Hum Reprod 2001 ;  16 : 2198-2205 [cross-ref]
Dodé C., Hardelin J.P. Kallmann syndrome Eur J Hum Genet 2009 ;  17 (2) : 139-146[Epub 2008 Nov 5].
Salenave S., Chanson P., Bry H., Pugeat M., Cabrol S., Carel J.C., and al. Kallmann’s syndrome: a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations J Clin Endocrinol Metab 2008 ;  93 : 758-763
Young J. Endocrine consequences of hemochromatosis Presse Med 2007 ;  36 : 1319-1325 [inter-ref]
Schoot D.C., Coelingh Bennink H.J., Mannaerts B.M., Lamberts S.W., Bouchard P., Fauser B.C. Human recombinant follicle-stimulating hormone induces growth of preovulatory follicles without concomitant increase in androgen and estrogen biosynthesis in a woman with isolated gonadotropin deficiency J Clin Endocrinol Metab 1992 ;  74 : 1471-1473 [cross-ref]
Tsilchorozidou T., Conway G.S. Uterus size and ovarian morphology in women with isolated growth hormone deficiency, hypogonadotrophic hypogonadism and hypopituitarism Clin Endocrinol (Oxf) 2004 ;  61 : 567-572 [cross-ref]
Kottler M.L., Chou Y.Y., Chabre O., Richard N., Polge C., Brailly-Tabard S., and al. A new FSH{beta} mutation in a 29-year-old woman with primary amenorrhea and isolated FSH deficiency: functional characterization and ovarian response to human recombinant FSH Eur J Endocrinol 2010 ;  162 : 633-641 [cross-ref]
Dodé C., Levilliers J., Dupont J.M., De Paepe A., Le Dû N., Soussi-Yanicostas N., and al. Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome Nat Genet 2003 ;  33 : 463-465[Epub 2003 Mar 10].
Dodé C., Teixeira L., Levilliers J., Fouveaut C., Bouchard P., Kottler M.L., and al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2 PLoS Genet 2006 ;  2 (10) : e175[Epub 2006 Sep 1].
Falardeau J., Chung W.C., Beenken A., Raivio T., Plummer L., Sidis Y., and al. Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice J Clin Invest 2008 ;  118 : 2822-2831 [cross-ref]
de Roux N., Genin E., Carel J.C., Matsuda F., Chaussain J.L., Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54 Proc Natl Acad Sci U S A 2003 ;  100 (19) : 10972-10976[Epub 2003 Aug 27].  [cross-ref]
Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, et al. The GPR54 gene as a regulator of puberty. N Engl J Med 2003;349(17):1614–27.
Topaloglu A.K., Reimann F., Guclu M., Yalin A.S., Kotan L.D., Porter K.M., and al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction Nat Genet 2009 ;  41 : 354-358 [cross-ref]
Guran T., Tolhurst G., Bereket A., Rocha N., Porter K., Turan S., and al. Hypogonadotropic hypogonadism due to a novel missense mutation in the first extracellular loop of the neurokinin B receptor J Clin Endocrinol Metab 2009 ;  94 : 3633-3639 [cross-ref]
Young J., Bouligand J., Francou B., Raffin-Sanson M.L., Gaillez S., Jeanpierre M., and al. TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans J Clin Endocrinol Metab. 2010 ; [Epub ahead of print].
Layman L.C., Cohen D.P., Jin M., Xie J., Li Z., Reindollar R.H., and al. Mutations in gonadotropin-releasing hormone receptor gene cause hypogonadotropic hypogonadism Nat Genet 1998 ;  18 : 14-15 [cross-ref]
de Roux N., Young J., Brailly-Tabard S., Misrahi M., Milgrom E., Schaison G. The same molecular defects of the gonadotropin-releasing hormone receptor determine a variable degree of hypogonadism in affected kindred J Clin Endocrinol Metab 1999 ;  84 : 567-572 [cross-ref]
Jongmans M.C., van Ravenswaaij-Arts C.M., Pitteloud N., Ogata T., Sato N., Claahsen-van der Grinten H.L., and al. CHD7 mutations in patients initially diagnosed with Kallmann syndrome – the clinical overlap with Charge syndrome Clin Genet 2009 ;  75 : 65-71 [cross-ref]



© 2010  Published by Elsevier Masson SAS.
EM-CONSULTE.COM is registrered at the CNIL, déclaration n° 1286925.
As per the Law relating to information storage and personal integrity, you have the right to oppose (art 26 of that law), access (art 34 of that law) and rectify (art 36 of that law) your personal data. You may thus request that your data, should it be inaccurate, incomplete, unclear, outdated, not be used or stored, be corrected, clarified, updated or deleted.
Personal information regarding our website's visitors, including their identity, is confidential.
The owners of this website hereby guarantee to respect the legal confidentiality conditions, applicable in France, and not to disclose this data to third parties.
Close
Article Outline