Hypogonadotropic hypogonadism (HH) is increasingly recognized as a genetically complex disorder characterized by incomplete penetrance and variable expressivity. Beyond classical monogenic inheritance, growing evidence supports an oligogenic model, whereby heterozygous variants in multiple genes regulating the hypothalamic–pituitary–gonadal (HPG) axis interact with developmental and systemic modifiers to determine clinical outcome.
To explore the role of heterozygous variants in HH-associated genes in shaping divergent phenotypes, including early-onset, reversible or persistent HH.
We describe three male patients with idiopathic HH who underwent detailed endocrine phenotyping, longitudinal clinical follow-up, neuroimaging, and whole-exome-sequencing. Genetic variants were interpreted according to ACMG-criteria and correlated with pubertal development, comorbidities, treatment response, and long-term gonadal axis function.
A 16-year-old male presented with delayed puberty and biochemically-confirmed HH, with normosmia and no structural abnormalities of the pituitary gland on magnetic-resonance-imaging. Whole-exome-sequencing identified heterozygous variants in WDR11 (NM_018117.12:c.371A>T, p.Asn124Ile; variant-of-uncertain-significance) and AIRE (NM_000383.4:c.769C>T,p.Arg257*; pathogenic). Following short-term testosterone priming, spontaneous recovery of gonadotropin and endogenous testosterone secretion was observed, consistent with reversible HH.
A 30-year-old male was diagnosed with HH in early adulthood (age 20). Whole-exome-sequencing revealed a heterozygous WDR11 variant (NM_018117.12:c.2246G>A,p.Arg749Gln; variant-of-uncertain-significance). Neuroimaging performed during childhood demonstrated generalized cortical atrophy, widened Sylvian fissures, and an atrophic brainstem, suggesting early neurodevelopmental involvement. Despite normosmia and the absence of structural pituitary abnormalities, pubertal development remained incomplete. The patient is currently maintained on long-term hormone- replacement-therapy.
A 48-year-old male presented with long-standing HH and eunuchoid body proportions. His medical history was notable for intermediate-β-thalassemia, diagnosed at the age of 3 years, requiring monthly blood transfusions until the age of 7, when transfusions were discontinued following splenectomy. At the age of 39, he was diagnosed with familial Mediterranean fever, treated with colchicine, and regular monthly transfusions were reinitiated. Whole-exome-sequencing identified a heterozygous FGFR1 variant (NM_001174063.3:c.266A>G,p.Gln89Arg; variant-of-uncertain significance). The patient exhibited persistent gonadotropin deficiency without spontaneous recovery and remains on lifelong hormone-replacement-therapy. Across cases, heterozygous variants were associated with markedly different clinical trajectories, suggesting that genetic background, systemic disease burden, and developmental modifiers collectively influence HPG axis integrity.
These observations support an oligogenic and modulatory model of HH, in which heterozygous variants in WDR11, AIRE, and FGFR1 may interact with clinical and developmental factors to determine disease severity and reversibility. This framework has important implications for prognosis, genetic counseling, and individualized therapeutic strategies, emphasizing the need for periodic reassessment of endogenous gonadal function in selected patients.
Maria Mateniadou, P. Makras, M. Koloutsou et al.· European Journal of Endocrin...· 0 citations
Diminished ovarian reserve (DOR) and poor ovarian response (POR) remain among the most challenging conditions in assisted reproductive technology, and no optimal stimulation strategy has been established. Clomiphene citrate (CC), a selective estrogen receptor modulator that augments endogenous gonadotropin secretion and modulates the intraovarian androgenic milieu, has been proposed as an adjuvant to reduce exogenous gonadotropin requirements. This mini-review summarizes clinical evidence published between January 2015 and March 2025 on the co-administration of CC with gonadotropins in women with DOR or POR undergoing IVF/ICSI. Eleven primary studies (four randomized controlled trials, six observational cohort studies and one before–after study) were identified through a structured, PRISMA-informed literature search. Across mild, standard, and high-dose regimens, CC co-administration consistently reduced total gonadotropin consumption and stimulation duration, whereas oocyte yield, clinical pregnancy, and live-birth rates were largely comparable to conventional protocols. Cost analyses suggest a meaningful reduction in the expenditure per treatment cycle, although the cost per delivery is driven predominantly by the low absolute success rates in this population. Careful monitoring of endometrial thickness is warranted given the anti-estrogenic effect of CC, and a freeze-all strategy may be preferable when endometrial development is suboptimal. In the wider context of adjuvant therapy for POR, CC occupies a position comparable to that of letrozole: it reduces treatment burden without demonstrable improvement in live birth. Larger, adequately powered multicentre randomized trials with live birth as the primary endpoint are needed to define the role of CC in this population.
Maria T. Papadopoulou, Miltiadis Badagionis, Fotios Vlahos et al.· Reproductive Medicine· 0 citations
Women suffering from PCOS display a variety of metabolic and hormonal abnormalities. Waist to height ratio (WHtR,), is considered as a valuable predictor of cardiovascular risk and central obesity.
To assess the association of WHtR with metabolic/hormonal profile in PCOS.
Data from 2201 PCOS women, mean age 25.0 years (21-29), BMI 24.7 kg/m2 (21.3-30.80) were analyzed. Participants were classified into three WHtR categories according to the established cut-offs (A: <0.50, B: 0.50-0.59, C: ≥0.60). Findings are presented before and after adjustment for age and BMI.
A gradual statistically significant increase was observed among subgroups regarding HOMA-IR [A: 1.5 (0.9-2.3), B: 2.7 (1.6-4.0), C: 4.2 (2.6-6.3)] and the existence of impaired glucose tolerance (IGT) [A: 7.3%, B: 12.4%, C: 24.0%], (P for trend <.001). The relationship of HOMA-IR with WHtR remained statistically significant (P < .001) even after adjustment for age and BMI. These subgroups were also associated with a progressively adverse lipid profile, characterized by higher triglyceride [A: 78 (58-102), B: 89 (67-111), C: 96 (75-142)mg/dl] and LDL cholesterol levels [A: 108 (86-133), B: 114 (94-139), C: 118.0 (98-133)mg/dl] and lower HDL cholesterol concentrations [A: 51(43-61), B: 51 (42-57), C: 45 (40-54)mg/dl], with strong linear trends across WHtR strata. Notably, the associations with triglycerides and HDL cholesterol persisted after adjustment for age and BMI (P < .001). Considering, hormonal profile, subgroups based on WHtR categories were associated with a progressive increase in free androgen index (FAI) [A: 4.97 (3.07-7.66), B: 7.49 (4.54-11.11), C: 9.38 (6.00-13.90)] and the prevalence of hirsutism [A: 55.5%, B: 61.8%, C: 69.3%] (P for trend <.001). Total testosterone levels showed a modest, but significant increase across WHtR strata, whereas DHEAS, D4 and 17OP concentrations did not differ significantly. Gonadotropins exhibited an inverse association with WHtR, with lower LH and FSH levels observed in higher WHtR categories, while TSH showed only a weak trend. In multivariate analyses, sugbroups were strongly associated with increased FAI values in a graded manner, and these associations remained statistically significant after adjustment for age and BMI (P < .001).
Multivariate analysis showed that WHtR constitutes a solid denominator of insulin resistance, dyslipidemia and hyperandrogenemia even after adjustment of age and BMI. These findings suggest that WHtR captures a distinct aspect of PCOS pathophysiology as it integrates both metabolic and androgenic interaction in PCOS and emerges as a pragmatic anthropometric marker for early metabolic risk stratification in PCOS.
S. Livadas, N. Angelopoulos, Jelica Bjekić Macut et al.· European Journal of Endocrin...· 0 citations
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