Premature ovarian failure (POF)

Premature ovarian failure is a syndrome characterised by cessation of menstrual function in women under 40 years of age against a background of decreased oestrogens and elevated gonadotrophins (FSH above 25 IU/L). POF incidence is about 1% in women of reproductive age. Aetiology is diverse: genetic (fragile X syndrome, gonadal dysgenesis), autoimmune, iatrogenic (after chemotherapy, radiotherapy, or ovarian surgery), idiopathic. Beyond fertility impairment, POF is associated with serious consequences: osteoporosis, early cardiovascular disease, depression, cognitive impairment, and reduced quality of life. Standard therapy — hormone replacement therapy with oestrogens and progestins — compensates for hormonal deficiency but does not restore fertility. Cell therapy is considered a way to act on ovarian regenerative processes and recover part of the lost function.

POF prevalence is estimated at 1% in women under 40 years and 0.1% in those under 30. The aetiological structure: idiopathic forms 60–80%, genetic 10–15% (FMR1 premutation, Turner-type gonadal dysgenesis, FOXL2, BMP15, NOBOX, FOXO3 mutations), autoimmune 5–30% (often as part of autoimmune polyendocrinopathy syndrome type 1, in association with Hashimoto thyroiditis or Addison disease), iatrogenic following alkylating chemotherapy or pelvic irradiation, after ovarian surgery or hysterectomy without ovarian preservation. Rare causes — viral infection (mumps oophoritis), metabolic (galactosaemia). In a substantial proportion of "idiopathic" POF, in-depth genetic work-up reveals previously unidentified mutations; targeted FMR1 screening is recommended in all women with POF regardless of family history.

Pathophysiologically, POF develops via two principal pathways. The first is depletion of the follicular pool: alkylating chemotherapy (cyclophosphamide) triggers massive apoptosis of primordial follicles via PI3K/Akt activation and the caspase cascade; pelvic radiotherapy at 8–10 Gy gonadal dose fully sterilises the ovary. The second pathway is disrupted folliculogenesis with a preserved pool: autoimmune oophoritis with antibodies against steroidogenic cells, gonadotrophin receptor mutations, and dysfunction of the hypothalamic-pituitary-ovarian axis. In both cases the result is reduced oestradiol and inhibin B production with compensatory FSH elevation. Oestrogen deficiency carries systemic consequences: accelerated cortical bone loss (2–5% per year before physiological menopausal age), endothelial dysfunction with atherosclerotic progression, vasomotor symptoms (hot flushes, night sweats), genitourinary syndrome, mood and cognitive changes. Anti-Müllerian hormone (AMH) is the best laboratory marker of ovarian reserve, reflecting the number of growing follicles and depending less on cyclical fluctuation than FSH.

Standard POF management follows international ESHRE 2016 and EMAS 2020 guidelines. Hormone replacement therapy is the foundation and must continue until physiological menopausal age (typically 50–51 years). Transdermal 17β-oestradiol (100 µg patch or gel) combined with cyclical progesterone or dienogest is preferred — this combination provides bone protection, atherosclerosis attenuation, vasomotor control, and mucosal support. NICE and ESHRE recommend individualised counselling on fertility, scheduled DEXA every 2–3 years, cardiovascular risk assessment, and sexual health review. Fertility options: IVF with donor oocytes — the most predictable route to pregnancy; experimental approaches — intra-ovarian platelet-rich plasma (PRP), in vitro activation (IVA) of dormant primordial follicles, autologous stem cells. Spontaneous pregnancy is possible in POF but its rate is 5–10% and unpredictable. Standard therapy effectively replaces hormones but does not regenerate the follicular reserve.

Mesenchymal cell therapy is considered a means of acting on ovarian regenerative processes. The clinical analysis of allogeneic UC-MSC transplantation in POF patients by Yan and colleagues (2020) demonstrated significant elevation of AMH, increased ovarian weight, and follicular number compared with chemotherapy controls. The systematic review in Frontiers in Endocrinology (2023) consolidated predominantly preclinical data showing reproducible improvements in follicle count, hormonal profile, and fertility in animal models; clinical translation is proceeding cautiously. According to ClinicalTrials.gov as of December 2023, 28 clinical trials of MSC therapy for POF are registered. Mechanistically, MSCs activate dormant primordial follicles via paracrine secretion of IGF-1, VEGF, and FGF; reduce the autoimmune component through IDO and TGF-β; restore ovarian stromal microcirculation; and protect remaining follicles from apoptosis.

The Hanshi United programme for POF builds on these data with emphasis on patient selection. The standard course is three procedures at 15–20 day intervals; the route is intravenous or combined (intravenous plus local intra-ovarian administration under ultrasound guidance in a specialised setting). Hormone replacement therapy is maintained — it supports bone and cardiovascular systems and does not conflict with the regenerative effect of MSCs. The greatest probability of a functional response lies in patients with short POF duration (up to 2–3 years from diagnosis), detectable AMH, preserved antral follicles on ultrasound, and autoimmune aetiology. In women with long-standing POF and depleted follicular reserve, the goals shift to improving quality of life, hormonal background, and bone density rather than restoring fertility; we communicate these expectations openly before the course.