RARE DISEASE
Rare female infertility
Rare female infertility
Rare female infertility
Drug discovery
1
drug
With orphan designation
Overview
Rare Female Infertility Overview
Rare female infertility encompasses conditions such as congenital uterine anomalies (e.g., septate uterus), premature ovarian insufficiency, severe endometriosis, and genetic disorders (e.g., Turner syndrome). These etiologies often require specialized diagnostic approaches, including imaging and genetic testing, and may involve advanced assisted reproductive technologies (ART) or surgical interventions for management [4][5][11][16].
Population
Affects ~16.2% of women with uterine abnormalities (polyps, fibroids, adhesions) and 10–15% with tubal disorders linked to untreated infections or endometriosis [4][5][14].
Premature ovarian insufficiency impacts 1% of women under 40, while severe endometriosis affects ~30–50% of infertile women [9][16].
Burden
Psychological distress, social stigma, and financial strain due to high treatment costs (e.g., IVF cycle costs $12,000–$25,000) [12][16][18].
Delayed diagnosis (e.g., endometriosis: 7–8 years average delay) exacerbates complications like chronic pain and reduced quality of life [16][20].
Disproportionate access barriers in low-resource settings, where <30% of countries prioritize fertility care [4][10].
Categories: rare infertility disorders
Research Papers
292 drug discovery papers related to Rare female infertility, with 3 first-in-class and 1 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
292 drug discovery papers related to Rare female infertility, with 3 first-in-class and 1 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-29 | Clinical pregnancy outcomes with assisted reproduction in patients with 17α-Hydroxylase/17, 20-lyase deficiency: a single center cohort study and integrated analysis with reported cases
Background 17α-hydroxylase/17, 20-lyase deficiency (17OHD) represents a rare form of congenital adrenal hyperplasia. Affected 46, XX females typically present with sexual development abnormalities, endocrine disturbances and infertility. While assisted reproductive technology (ART) enables pregnancies in these patients, our knowledge about optimal management strategies and pregnancy outcomes remains limited. Methods We conducted a retrospective cohort study of women with 17OHD who achieved clinical pregnancy at our center between January 2009 and August 2025, followed until December 2025. Moreover, we performed a systematic review of published cases, extracting and analyzing demographic, clinical, laboratory, treatment, and outcome data. Results Among 20 female patients with 17OHD at our center, six desired fertility and three achieved clinical pregnancy with ART. Combined with 17 reported cases from 12 studies, a total of 20 pregnancies resulted in 23 live births. Median age at pregnancy preparation was 29 (range 21–42) years. The prevalence rates of hypertension and adrenal insufficiency were 25.0% (5/20) and 50.0% (10/20), respectively. Median follicular-phase progesterone was 20.8 nmol/L. Seventeen women conceived via frozen embryo transfer (FET) following ovarian stimulation, including nine with GnRH agonists (GnRHa), six with progestin-primed ovarian stimulation, one with GnRH antagonists, and one with GnRHa short protocol, respectively. Nearly 95% (18/19) participants received glucocorticoids before embryo transfer. Pregnancy complications (including gestational hypertension, diabetes, preeclampsia, and HELLP syndrome) occurred in 46.2% (6/13) cases. Only 25% (5/20) of the participants had term vaginal deliveries. All five offspring that were followed up developed normally. Conclusions For women with 17OHD, a treatment protocol combining glucocorticoid-assisted progesterone suppression with FET represents a viable strategy to achieve pregnancy. However, such patients face high risks of adverse maternal and perinatal outcomes, requiring multidisciplinary management throughout gestation.
2026-04-01 | Comment on “Farnesylation-Dependent Kinetochore Targeting of Centromere Protein F Is Essential for Oocyte Meiotic Progression and Female Fertility”
Successful cell division during meiosis is dependent on accurate chromosome segregation; the role of centromeres, kinetochores, and spindle microtubules is well characterized in mitosis, but the role of certain proteins surrounding them remains uncertain in meiosis. This is important to understand because the arrest of maturation of oocytes is a common origin of female infertility, but the mechanisms for this are largely unknown. This study was designed to assess the regulatory mechanism of the farnesylation of centromere protein F on its meiotic function as well as evaluate any association between mutations in centromere protein F and female oocyte maturation disorders. This study used oocyte microinjection, western blotting, co-immunoprecipitation, and immunofluorescence to characterize the role of centromere protein F. During mitosis, this protein assists in chromosome segregation, but it is currently unknown if its role remains the same during meiosis. This study used a mouse model to explore both genetic and pharmacologic methods of farnesylation, and to verify the mechanism of mutations in oocyte maturation. Microinjection of centromere protein F siRNA reduced maturation rates significantly, with many halting maturation at metaphase I ( P <0.05). Farnesylation likewise reduced the rate of oocyte maturation ( P <0.01), and additionally weakened the interationc between centromere protein F and Aurora kinase B, which was confirmed by co-immunoprecipitation ( P <0.01). Farnesylation also disrupted kinetochore localization, contributing to the arrest of oocyte maturation. Immunofluorescence analysis further showed that centromere protein F localized at kinetochores by metaphase I, causing arrested development. Screening human patients with infertility resulted in the identification of 4 individuals with rare heterozygous variants in the CENP-F gene that were associated with the arrest of oocyte maturation. When testing centromere protein F derived from patients who were identified to have a genetic mutation in this protein, microinjection of the patient-derived centromere protein F also caused significantly reduced maturation in mouse oocytes ( P <0.01). Two identified mutations reduced the fanesylation of centromere protein F as well as disrupted kinetochore localization and damaged the Aurora kinase B interaction. These results indicate that there is a direct association between centromere protein F mutations and infertility, specifically the arrest of oocyte maturation during meiosis. These findings contribute evidence to the controversy surrounding the influence of farnesylation on the localization of CENP- F, with some previous studies showing no effect of farneslyation and others showing a direct interaction between molecules that is dependent on farneslyation. This study emphasizes the need for further clinical research to validate the pathology of these mutations in diverse populations. Future studies should also attempt to ethically validate the results of these mouse models in human models and examine other possible mechanisms for arrested maturation of oocytes such as disruption of microtubule binding. (Summarized from Zhong O, Wang C, Zhang J, et al. Farnesylation-dependent kinetochore targeting of centromere protein F is essential for oocyte meiotic progression and female fertility. Am J Obstet Gynecol. 2026;234:116-140. doi: 10.1016/j.ajog.2025.08.031)
2026-03-25 | FEMALE GENITAL TUBERCULOSIS: A NEGLECTED CAUSE OF INFERTILITY IN DEVELOPING COUNTRIES
Background: Female genital tuberculosis (FGTB) is an important form of extrapulmonary tuberculosis and a leading, yet often under recognized, cause of infertility in women of reproductive age, particularly in developing countries. The disease is frequently asymptomatic and under diagnosed due to its nonspecific clinical presentation, contributing to delays in management and poor reproductive outcomes. Methods: This review summarizes current knowledge on the epidemiology, pathogenesis, clinical manifestations, diagnostic approaches, treatment strategies, drug resistance, and public health implications of FGTB. Data were synthesized from epidemiological studies, clinical reports, and molecular diagnostic research. Results: FGTB primarily affects the fallopian tubes (90–100%), followed by the endometrium (50–60%) and ovaries (20–30%), with rare involvement of the cervix, vagina, or vulva. Clinical presentation ranges from infertility, menstrual irregularities, and pelvic pain to asymptomatic cases. Diagnosis requires a combination of imaging (hysterosalpingography, ultrasonography, laparoscopy), histopathology, microbiological testing (Ziehl–Neelsen staining, culture), molecular methods (PCR, gene amplification, BACTEC), and immunological tests. Standard antitubercular therapy (ATT) for 6–9 months remains the cornerstone of treatment, with surgical intervention reserved for complicated cases. Drug-resistant tuberculosis, particularly multidrug-resistant TB (MDR-TB), poses a significant therapeutic challenge. FGTB causes structural and functional damage to the reproductive tract, resulting in tubal obstruction, endometrial destruction, pelvic adhesions, and ovarian dysfunction, leading to infertility in 40–80% of affected women, often necessitating assisted reproductive techniques such as in vitro fertilization. Conclusion: FGTB represents a significant reproductive health burden in endemic regions. Early detection through improved awareness, screening of infertile women, and use of molecular diagnostics is essential to prevent irreversible reproductive damage. Strengthening tuberculosis control programs and public health strategies is critical for reducing the incidence of this neglected cause of female infertility.
2026-06-29 | Clinical pregnancy outcomes with assisted reproduction in patients with 17α-Hydroxylase/17, 20-lyase deficiency: a single center cohort study and integrated analysis with reported cases
Background 17α-hydroxylase/17, 20-lyase deficiency (17OHD) represents a rare form of congenital adrenal hyperplasia. Affected 46, XX females typically present with sexual development abnormalities, endocrine disturbances and infertility. While assisted reproductive technology (ART) enables pregnancies in these patients, our knowledge about optimal management strategies and pregnancy outcomes remains limited. Methods We conducted a retrospective cohort study of women with 17OHD who achieved clinical pregnancy at our center between January 2009 and August 2025, followed until December 2025. Moreover, we performed a systematic review of published cases, extracting and analyzing demographic, clinical, laboratory, treatment, and outcome data. Results Among 20 female patients with 17OHD at our center, six desired fertility and three achieved clinical pregnancy with ART. Combined with 17 reported cases from 12 studies, a total of 20 pregnancies resulted in 23 live births. Median age at pregnancy preparation was 29 (range 21–42) years. The prevalence rates of hypertension and adrenal insufficiency were 25.0% (5/20) and 50.0% (10/20), respectively. Median follicular-phase progesterone was 20.8 nmol/L. Seventeen women conceived via frozen embryo transfer (FET) following ovarian stimulation, including nine with GnRH agonists (GnRHa), six with progestin-primed ovarian stimulation, one with GnRH antagonists, and one with GnRHa short protocol, respectively. Nearly 95% (18/19) participants received glucocorticoids before embryo transfer. Pregnancy complications (including gestational hypertension, diabetes, preeclampsia, and HELLP syndrome) occurred in 46.2% (6/13) cases. Only 25% (5/20) of the participants had term vaginal deliveries. All five offspring that were followed up developed normally. Conclusions For women with 17OHD, a treatment protocol combining glucocorticoid-assisted progesterone suppression with FET represents a viable strategy to achieve pregnancy. However, such patients face high risks of adverse maternal and perinatal outcomes, requiring multidisciplinary management throughout gestation.
2026-04-01 | Comment on “Farnesylation-Dependent Kinetochore Targeting of Centromere Protein F Is Essential for Oocyte Meiotic Progression and Female Fertility”
Successful cell division during meiosis is dependent on accurate chromosome segregation; the role of centromeres, kinetochores, and spindle microtubules is well characterized in mitosis, but the role of certain proteins surrounding them remains uncertain in meiosis. This is important to understand because the arrest of maturation of oocytes is a common origin of female infertility, but the mechanisms for this are largely unknown. This study was designed to assess the regulatory mechanism of the farnesylation of centromere protein F on its meiotic function as well as evaluate any association between mutations in centromere protein F and female oocyte maturation disorders. This study used oocyte microinjection, western blotting, co-immunoprecipitation, and immunofluorescence to characterize the role of centromere protein F. During mitosis, this protein assists in chromosome segregation, but it is currently unknown if its role remains the same during meiosis. This study used a mouse model to explore both genetic and pharmacologic methods of farnesylation, and to verify the mechanism of mutations in oocyte maturation. Microinjection of centromere protein F siRNA reduced maturation rates significantly, with many halting maturation at metaphase I ( P <0.05). Farnesylation likewise reduced the rate of oocyte maturation ( P <0.01), and additionally weakened the interationc between centromere protein F and Aurora kinase B, which was confirmed by co-immunoprecipitation ( P <0.01). Farnesylation also disrupted kinetochore localization, contributing to the arrest of oocyte maturation. Immunofluorescence analysis further showed that centromere protein F localized at kinetochores by metaphase I, causing arrested development. Screening human patients with infertility resulted in the identification of 4 individuals with rare heterozygous variants in the CENP-F gene that were associated with the arrest of oocyte maturation. When testing centromere protein F derived from patients who were identified to have a genetic mutation in this protein, microinjection of the patient-derived centromere protein F also caused significantly reduced maturation in mouse oocytes ( P <0.01). Two identified mutations reduced the fanesylation of centromere protein F as well as disrupted kinetochore localization and damaged the Aurora kinase B interaction. These results indicate that there is a direct association between centromere protein F mutations and infertility, specifically the arrest of oocyte maturation during meiosis. These findings contribute evidence to the controversy surrounding the influence of farnesylation on the localization of CENP- F, with some previous studies showing no effect of farneslyation and others showing a direct interaction between molecules that is dependent on farneslyation. This study emphasizes the need for further clinical research to validate the pathology of these mutations in diverse populations. Future studies should also attempt to ethically validate the results of these mouse models in human models and examine other possible mechanisms for arrested maturation of oocytes such as disruption of microtubule binding. (Summarized from Zhong O, Wang C, Zhang J, et al. Farnesylation-dependent kinetochore targeting of centromere protein F is essential for oocyte meiotic progression and female fertility. Am J Obstet Gynecol. 2026;234:116-140. doi: 10.1016/j.ajog.2025.08.031)
2026-03-25 | FEMALE GENITAL TUBERCULOSIS: A NEGLECTED CAUSE OF INFERTILITY IN DEVELOPING COUNTRIES
Background: Female genital tuberculosis (FGTB) is an important form of extrapulmonary tuberculosis and a leading, yet often under recognized, cause of infertility in women of reproductive age, particularly in developing countries. The disease is frequently asymptomatic and under diagnosed due to its nonspecific clinical presentation, contributing to delays in management and poor reproductive outcomes. Methods: This review summarizes current knowledge on the epidemiology, pathogenesis, clinical manifestations, diagnostic approaches, treatment strategies, drug resistance, and public health implications of FGTB. Data were synthesized from epidemiological studies, clinical reports, and molecular diagnostic research. Results: FGTB primarily affects the fallopian tubes (90–100%), followed by the endometrium (50–60%) and ovaries (20–30%), with rare involvement of the cervix, vagina, or vulva. Clinical presentation ranges from infertility, menstrual irregularities, and pelvic pain to asymptomatic cases. Diagnosis requires a combination of imaging (hysterosalpingography, ultrasonography, laparoscopy), histopathology, microbiological testing (Ziehl–Neelsen staining, culture), molecular methods (PCR, gene amplification, BACTEC), and immunological tests. Standard antitubercular therapy (ATT) for 6–9 months remains the cornerstone of treatment, with surgical intervention reserved for complicated cases. Drug-resistant tuberculosis, particularly multidrug-resistant TB (MDR-TB), poses a significant therapeutic challenge. FGTB causes structural and functional damage to the reproductive tract, resulting in tubal obstruction, endometrial destruction, pelvic adhesions, and ovarian dysfunction, leading to infertility in 40–80% of affected women, often necessitating assisted reproductive techniques such as in vitro fertilization. Conclusion: FGTB represents a significant reproductive health burden in endemic regions. Early detection through improved awareness, screening of infertile women, and use of molecular diagnostics is essential to prevent irreversible reproductive damage. Strengthening tuberculosis control programs and public health strategies is critical for reducing the incidence of this neglected cause of female infertility.
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Drug Discovery Landscape
1 orphan drug designation for Rare female infertility.
1 orphan drug designation for Rare female infertility.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
autologous adult bone marrow-derived and unexpanded CD133+ hematopoietic stem cells (CD133+ BMDSCs) mobilized from peripheral blood (PB) | cell therapies | FDA | 2019-02-01 | — | Asherman Therapy S.L.U. |
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