Sex Hormone Treatment for Female Children and Young Adults with Disorders Affecting Hypothalamic, Pituitary, and Ovarian Function Open Access

Structural and functional integrity of the hypothalamic-pituitary-ovarian (HPO) hormonal axis is essential for normal pubertal and psychosocial development, regular menstrual cycling, fertility, optimal wellbeing, cardiovascular and bone health [1]. A variety of disorders may adversely affect normal functioning of the HPO axis. Classification into primary ovarian or secondary hypothalamic-pituitary failure is a useful framework for a diagnostic approach. The clinical consequences encompass complete, partial or intermittent hypogonadism, the third being related to relapsing and remitting chronic disease states. Females with disturbed HPO-functioning may require sex hormone treatment for one or a combination of the following purposes: (i) hormone replacement therapy (HRT) to induce and progress through puberty and/or to maintain normal young adult female hormone status; (ii) menstrual management, and (iii) contraception, as young women with endocrine conditions are as likely as their peers to be sexually active and at potential risk for unplanned pregnancy.

An effective, professional relationship must be established to ensure appropriate use of sex hormones. Based on this relationship, challenges including consideration for transition from HRT to accommodate contraceptive needs and concerns related to misconceptions about HRT generated in the popular press (such as undifferentiated statements on HRT being dangerous) can be addressed. Additionally, active communication channels with primary care and other physicians are essential to optimize management of complex medical conditions [2].

In this non-systematic, narrative mini-review, we aim to provide an overview of sex hormone treatment for females with disordered function of the HPO axis from pubertal induction until age 30 years. HRT for older women is beyond the scope of this paper. We discuss pubertal induction and HRT, menstrual management and contraception for females with complete gonadal insufficiency and add relevant information for females with partial or intermittent gonadal insufficiency related to chronic diseases. This mini-review aims to support the reader in understanding the complex and evolving needs of young women with these disorders with nuances for optimal provision of sex hormone support as required. A literature search on PubMed using terms including hypothalamic-pituitary hypogonadism, gonadal or ovarian failure, premature ovarian insufficiency, chronic disease, ovarian failure, puberty, pubertal induction, HRT, abnormal uterine bleeding (AUB), menstrual irregularities, menstrual management, and contraception was performed. Study findings relevant for females up to 30 years, published over the last 20 years were integrated with clinical experience of the authors.

Hypogonadism in adolescence may clinically manifest with failure to enter puberty, with pubertal arrest, or with primary or secondary amenorrhea. A careful history, including family history for similar disorders, complete physical examination including evidence of dysmorphism, midline defects and pubertal status, together with appropriate biochemistry and imaging will help elucidate a cause and define treatment options [3]. Primary ovarian insufficiency or hypergonadotropic hypogonadism (see Table 1) is characterized by high serum gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]), and low/normal estradiol (E2) levels. Secondary (hypogonadotropic) hypogonadism (see Table 2) is characterized by low serum FSH, LH, and E2 levels. Functional hypogonadotropic hypogonadism due to excessive stress, eating disorders, active inflammatory bowel disease (IBD) or relative energy deficiency in sports (RED-S), characterized by low FSH, LH, and low E2 is potentially reversible [4]. Pubertal management is similar for both primary and secondary hypogonadism. Principles of care will be outlined for both, with specific detail for each condition that causes complete or partial/intermittent gonadal insufficiency.

Females with complete gonadal insufficiency due either to primary or secondary hypogonadism should commence with low dose estrogen replacement for pubertal induction by age 11–12 years [13, 14]. Past practice of delaying pubertal induction until 15 or older to promote growth in adolescents with Turner syndrome (TS) resulted in reduced final height and insufficient bone mass accrual. This approach has been abandoned [15]. In case of pubertal arrest, estrogen replacement is commenced at a dosage in keeping with the achieved degree of pubertal development. The main aims of pubertal induction and completion are to mimic the normal trajectory of puberty, to achieve optimal pubertal growth, feminization, adult uterine volume, to accrue adequate bone mass and optimize cardiovascular health and quality of life (see Fig. 1) [3, 8, 16]. For pubertal induction, natural estrogen as 17β-estradiol (E2) [17] is recommended rather than synthetic estrogen (EE), due to a markedly lower induction of renin substrate (see Table 3). If convenient, acceptable, and available for the adolescent, E2 is preferably applied as a transdermal patch or gel to avoid hepatic first-pass and consequent pro-coagulopathic effects from oral, natural estrogen agents. Although these complications are relatively rare in a young population, they are specifically important for congenital or acquired pro-coagulopathic disorders, e.g., factor V Leiden mutation, protein C/S or IBD, or in severe disabilities where intake may be problematic and limited mobility may increase risk for venous thromboembolism (VTE). The VTE risk related to oral synthetic estrogens is discussed in more detail under the relevant section of contraception.

After all, the preference of the adolescent for pills, patches, or gels is most relevant to ensure compliance. E2-patches release 17β-estradiol continuously over 24 h and can be held in place for 3–4 days, some for 7 days before replacement [18]. They can be cut in portions to achieve required low starting doses. However, there are significant brand-related differences in utility and stability depending on size and storage temperature [19]. A possible regimen for E2 patches might be to start with a quarter patch for half the week or half a pill of 1 mg E2 every second day with up-titration at 6-monthly follow-up visits. After a total of 2.5 years, an adult dose 50 µg as patch or 2 mg oral is usually reached and considered sufficient for adequate bone and cardiovascular health [3, 18].

Despite clear biochemical evidence of primary or secondary gonadal dysfunction, some girls will enter puberty spontaneously, with later pubertal arrest, in which case E2 dose should be in keeping with the degree of pubertal development that has been achieved. If regular breakthrough bleeding occurs during pubertal induction, assuming regular use of medication, or after 2.5 years of E2, a cyclical progestin (synthetic form of progesterone) or micronized progesterone (bioidentical hormone to endogenously produced progesterone) must be added for regular menstrual shedding to avoid endometrial hyperplasia and consequent later risk of endometrial cancer [18]. The frequency of cycling may be chosen 1–3 monthly, adding progestins or micronized progesterone for 12–14 days (e.g., medroxyprogesterone acetate 10 mg, norethisterone 5 mg per day, dihydrogesterone 10 mg once or twice daily; micronized progesterone 100 mg twice daily), a withdrawal bleed occurring usually 1–3 days after cessation of progestin. Progestins or micronized progesterone can also be used continuously (e.g., medroxyprogesterone acetate 5 mg, dydrogesterone 10 mg or micronized progesterone 100 mg once or twice daily) to provide stable hormone levels without regular bleeding. It is important to stress to the patient and family that the E2 should be continuous and not ceased at time of progestin use or bleeding, to obviate bone loss and symptoms related to hypogonadism occurring during E2 withdrawal.

Conditions need special care where ovarian function may fluctuate depending on physical health and weight status, such as in severe IBD, eating disorders, in infiltrative conditions such as iron deposition with transfusion requirement, galactosemia or in severe neurodevelopmental disabilities affecting nutritional status. Conditions where progressive loss of gonadal function occurs (exposure to radiation, gonadotoxins, or infiltrative disorders) require regular assessment to avoid late diagnosis and management, where other complex care needs frequently override recognition of this important aspect of care.

In women with IBD, particularly with active Crohn’s disease and malabsorption, the HPO axis usually switches off, causing pubertal delay, arrest or secondary amenorrhoea. Given that ∼50% of bone mass accrual occurs during the pubertal years, attention to HRT, if needed, is of extreme importance. Oral HRT should be avoided, due to erratic absorption and due to pro-coagulopathic risk. Transdermal E2 can be used for completion of puberty and for intermittent support throughout adolescence and adulthood during active disease. In post-menarchal young women, a nonfunctioning HPO axis is easily identifiable, the marker of HRT need being onset of oligo-amenorrhea, usually at a time of flare up/weight loss.

In women with eating disorders, in addition to weight recovery, hormonal support is frequently required to initiate and/or complete pubertal progress. Oral E2 is often not accepted by affected girls who may have irrational fear of weight gain, whereas transdermal E2 is usually accepted and assists in completing linear growth, feminization, bone mass accrual, and improving mental health outlook [20].

In women with congenital anemia requiring transfusion (e.g., Thalassemia major, Blackfan Diamond syndrome), progressive hypothalamic-pituitary deposition of iron frequently causes secondary hypogonadism. This may present as pubertal delay, arrest or as later primary hypogonadism due to gonadal infiltration, defined by abnormality of gonadotropins and low E2, failure to proceed through puberty or to maintain HPO function, together with failure of bone mass accrual and/or bone loss.

Female cancer survivors having been treated with gonadotoxins (particularly alkylating agents and/or pelvic radiation) are at high risk for initial intermittent loss of HPO function with highly variable gonadotropins, only progressing later to primary hypogonadism. Early recognition and intervention reduce physical and psychologic disability and distress.

Girls with severe developmental disabilities (congenital brain malformations/perinatal insults [hypoxic ischemic encephalopathy]) may enter puberty spontaneously; however, those with neurodevelopmental disabilities affecting nutrition may enter puberty earlier or late [21]. Fears of parents and/or carers about the perception and expression of sexuality and apprehensions of the onset of menstrual cycling are common causes for presentations to gynecologists or pediatricians well before menarche. It is important to acknowledge and address these concerns and providing reassurance that management is available to address needs. We recommend advising on the many mental and physical health advantages of normal puberty, including maturation of the adolescent’s personality, accrual of bone mass, and the optimization of cardiovascular health [20, 22]. Once adolescents with gonadal insufficiency have completed puberty, issues related to AUB and individual requirements for contraception may need to be addressed as follows.

Regular menstrual cycling is a useful marker for overall endocrine health. AUB in females might provide a clue to an underlying condition with impact on normal HPO functioning, such as hyperandrogenism, IBD, or thyroid disorders. Following an overview, management options for AUB, if contraception is not required are discussed with specific information for common conditions affecting HPO-functioning.

Overall, AUB is defined as any aberration in menstrual frequency, duration, regularity, or volume and affects up to 30% of menstruating women with higher incidence during adolescence [23]. Oligomenorrhea and heavy menstrual bleeding are the most common reasons for attendance to a gynecologist [24]. A thorough history based on a cycle calendar, information on duration of AUB from time of menarche, eating habits, and physical activity usually provide sufficient information to differentiate normal from AUB [25]. Menstrual irregularities within the first 12–18 months after menarche commonly reflect luteal insufficiency-related anovulatory cycles and missing progesterone [26], not AUB. However, cycle lengths <21 days (i.e., polymenorrhea) or >35 days (i.e., oligomenorrhea) 2 years after menarche may warrant further investigation.

If a contraindication for estrogen therapy is present and/or contraception not required, cyclic administration of progestin alone might be used for cycle control. We suggest that for most forms of AUB good cycle control can generally be achieved with use of 12–14 days of intermittent oral progestin every 2–3 months, the choice being largely related to avoidance of individual patient side effects (e.g., medroxyprogesterone acetate 10 mg or norethisterone acetate 10 mg for 14 days). Levonorgestrel might be used where progestin side effects are prominent.

A study of adolescent females with TS undergoing pubertal induction with transdermal estrogen investigated the prevalence of AUB, revealing that a third of the participants had AUB [27], similar to the prevalence of AUB in the general population [23]. Key factors associated with increased risk for AUB in this study were progestin dose of less than 200 mg of micronized progesterone, a continuous rather than a sequential progestin regimen, and poor adherence to HRT. The authors suggested to increase the dose and duration of progestin (i.e., 200 mg micronized progesterone over at least 10 days) and advised for an intermittent progestin regimen for regular withdrawal bleeds. This advice is also valid for other non-genetic forms of gonadal insufficiency. Increasing estrogen dose is rarely required. Gynecologic referral should be considered if these simple measures do not resolve the AUB.

Hyperandrogenic disorders include clinical entities from polycystic ovary syndrome (PCOS) to nonclassical classical adrenal hyperplasia (CAH) and CAH, all of which present with symptoms related to excessive androgen production and/or action. In women with CAH and nonclassical CAH, optimal glucocorticoid replacement must be prioritized and is likely to result in normal cycling unless the duration of severe hyperandrogenism has been prolonged over years.

For women with PCOS and menstrual irregularities, current recommendations include lifestyle changes followed by problem-oriented pharmacological treatment. Metformin might be an option to assist with weight management by reducing insulin resistance, with improved regularity of ovulation reported. This effect is beneficial in both the adolescent setting and in adulthood where its use to improve fertility prospects is well established [28, 29]. Additional options for AUB management – notwithstanding contraception, which is discussed in the next section – include intermittent oral progestins as discussed above.

Adolescents and young adult women with obesity are at higher risk for insulin resistance, which is associated with hyperandrogenism [30]. Peripheral aromatization of high levels of androgens and decreased levels of sex hormone binding globulin in women with obesity both explain higher circulating levels of estrogen [31]. Higher estrogen levels disturb normal ovulation and are associated with an increased risk for endometrial hyperplasia, endometrial atypia, and endometrial cancer [32]. Lifestyle interventions are first-line treatment as 5–10% weight loss within 6 months has been reported to normalize cycling [33]. Pharmacological control of menses with cyclic progestin may be provided if contraception is not wished. However, persistent AUB in young women with obesity despite hormonal therapy requires gynecology referral to investigate a structural, endometrial pathology such as endometrial polyps, atypical hyperplasia, or cancer.

AUB is common for women with undiagnosed, and with established but poorly controlled diabetes mellitus type 1 (T1DM) and type 2 (T2DM), IBD, or thyroid disorders [34‒36]. Overall, management of the underling condition is prioritized, followed by subsequent management of AUB as in healthy women at reproductive age for which we refer to the American College of Obstetricians and Gynecologists [37].

Most adolescent females with significant disabilities enter puberty spontaneously, however, some may present with precocious, prolonged, delayed, or arrested puberty [38]. Related to the chronic and deteriorating overall nature of their underlying condition, hypogonadism and subsequent bone loss may evolve [38, 39]. Even if HPO function is not affected, adolescent females with significant disabilities require management of menstrual cycling related to hygiene management or family and carer difficulties to accept “normal” bleeding. According to a retrospective cohort study to investigate benefits from premenarchal reproductive counselling, 80% desired hormonal management of menstrual cycling [40]. Hence, in female adolescents, deviations in timing and duration of puberty as well as a cycle history and the overall capacity to manage regular bleeding by the individual or the carer thereof should be assessed routinely. The authors advocate for a low-threshold referral to a pediatric endocrinology or adolescent gynecology service for assessment and management of HPO function to ensure optimal bone and cardiovascular health, to promote emotional maturity and to facilitate menstrual management for the family and/or carers. As per our experience, these visits serve an important opportunity to inform the families about physical and mental health aspects from sex hormones. In terms of management, the choice of medication must be individualized. Although combined oral contraceptives (COCs) are often prescribed as first line, young women with major disabilities have complex competing needs such as anticonvulsant use interfering with estrogen excretion, potential missed medication, care and school difficulties with hygiene. Intrauterine devices (IUD) use is increasingly accepted for menstrual control, contraception, and convenience, with a 5+ year turnaround for replacement [38, 41]. Subcutaneous progestin rod use is difficult in this group due to lack of understanding, pain on insertion, with low chance of amenorrhea, or polymenorrhea, high risk of continued bleeding and significant adverse side effects on mood, often requiring removal.

For adolescents with gonadal insufficiency, it is important to discuss fertility potential and contraception before they are sexually active. Whilst women with gonadal insufficiency may wish to conceive, they may also be unaware of variations in their fertility potential and potential risk for unplanned pregnancy, as HRT does not prevent ovulation.

Available hormonal contraceptive options are COCs, hormonal vaginal rings, contraceptive patches, long-acting 3-monthly injections and long-acting reversible contraception (LARC) including hormonal and nonhormonal intrauterine devices and subcutaneous depot progestin as implants [42]. Progestin-only oral mini pills (POPs) vary in efficacy for contraception: newer formulations including desogestrel and drospirenone are close to COCs as they prevent pregnancy by inhibiting ovulation [43], whereas older formulations may offer some protection in the postpartum period but are highly dependent on compliance and are not generally considered safe in young women as they do not offer contraception at a level above that of barrier methods.

COCs might be an option for contraception for young women with hypogonadism; however, several aspects are important: first, the ethynyl sidechain in EE-containing COCs are associated with higher blood pressure, worse renal function and higher risk for dyslipidemia and VTE compared to E2 in HRT in women with hypogonadism [44]. Regarding the risk for VTE, the absolute risk associated with COCs is considered low, at approximately 7 per 10,000 women years, is lower at younger age of usage, and should be put in relation to the risk for VTE during (unplanned) pregnancy, that is ∼20 per 10,000 women years [45, 46]. Also, risk increases from natural (E2) to synthetic forms (EE), is higher with higher systemic dose of EE (particularly at dose beyond 35 μg of EE in COCs) and depends on the progestin component: compared to nonusers, the mean risk for VTE is 3.2 times greater for first-generation progestins (e.g., norethindrone), 2.8 times greater for 2nd generation progestins (e.g., levonorgestrel and norgestrel) and 3.8 times greater for 3rd and 4th generation progestins (e.g., desogestrel, drospirenone) [47, 48]. Consequently, if a personal and family history of migraine with aura, deep venous thrombosis or pulmonary embolism is present [49], progestin-only or nonhormonal contraceptive agents are recommended. Compared to nonusers, levonorgestrel-IUD, etonogestrel-implants, and oral norethindrone showed no increased odds risk for VTE, whereas oral medroxyprogesterone acetate, oral norethindrone acetate, and depot medroxyprogesterone acetate revealed adjusted mean odds ratios for VTE between 1.98 and 3.00 [50]. LARCs are an excellent choice due to their high efficacy, safety, and high satisfaction rate. The progestin-bearing IUD provides up to 5–8 years of contraception, with amenorrhea in 95%, little side effects as the progestin dose is very low and mode of action confined to minimization of the endometrium [51]. Extrusion rate is very low. However, females with disabilities may require brief general anesthesia for IUD-implantation. Important to note that maintenance (add back) E2 (see Table 3 for options) needs to be added for young women with complete gonadal failure or those on high dose progestins (e.g., depot progestins) as they switch off HPO-function [52].

Conventional use of COC utilizes 3 weeks of EE and progestin, 1 week of lactose only pills. Thus, women gonadal insufficiency will experience estrogen deficiency symptoms including bone loss for 1 week in every four [53, 54] and adverse emotional effects of oestrogen withdrawal for 7 days of every 28. To avoid these effects related to estrogen withdrawal, preferred regimes utilize 3 monthly cycles or continuous COC.

Whilst information provision regarding increase in relative risk for breast cancer in premenopausal women using oral hormonal contraception versus nonusers is mandatory, perspective is important. Overall, the risk is low and amongst other factors dependent on the women`s age, whether a combined hormonal or progestin-only regimen was used, and on duration of exposure. A large prospective cohort study involving all Danish women revealed that the increase in risk translates into one additional case of invasive breast cancer per every 50,000 women below 35 years, whereas there was one additional case in every 7,690 when the whole population (aged 15–49 years) was considered [55].

For progestin only versus combined hormonal contraception, a recent nationwide prospective cohort study involving all Swedish women aged 15–34 years showed no increased risk for breast cancer development in current users of any combined hormonal contraception compared to nonusers, whereas progestin-only users had an increased incident rate ratio of 1.32 (95% CI: 1.20–1.45) [56].

Lastly, there is sound evidence for an increase in risk with longer duration of hormonal contraception usage, which disappears within 5–10 years after hormonal contraception is stopped [55‒57]. This slight increase in breast cancer risk related to hormonal contraception needs to be balanced against a favorable risk reduction for ovarian, endometrial, and colon cancer, resulting in a slightly reduced overall cancer risk in long-term hormonal contraceptive users. Also with effective contraception, there is no maternal mortality rate that was 2015 reported with 26.4 deaths per 100,000 US women double the risk of developing breast cancer [58].

Recipients of gonadotoxins and/or hypothalamic-pituitary radiation need advice on potentially changing from HRT to contraception when sexually active. The chance for cancer survivors to retain fertility depends on the received treatment and is overall least likely for those who received alkylating chemotherapeutic agents, ovarian/pelvic irradiation, total body irradiation or hematopoietic stem cell transplantation [59]. However, recovery from ovarian insufficiency and spontaneous fertility have been reported many years after established ovarian insufficiency, even after hematopoietic stem cell transplantation with total body irradiation [60]. Childhood cancer survivors have lower reported usage of contraception and the methods used are reported less effective when compared to their healthy counterparts, possibly related to insufficient awareness and counselling or with well-recognized risk-taking behaviors [61]. Recipients of hypothalamic-pituitary radiation may also have erratic and inconsistent loss of gonadotropins, rendering them at potential risk.

Women with idiopathic primary ovarian insufficiency may be associated with intermittent ovarian activity with a reported pregnancy rate between 4 and 6% [62]. Similar, 5–10% of women with TS may have spontaneous puberty, with 2–5% reports of spontaneous pregnancy [63]. Women with hypogonadism may also have additional pregnancy-related risks, particularly cardiac risks following TS-related structural cardiac abnormalities, anthracycline treatment for childhood cancer or teratogenic risks due to exposure to immunosuppressives (e.g., azathioprine) for the treatment of chronic inflammatory conditions.

Many girls and women with common endocrine conditions including hyperandrogenism, obesity, T1DM, and T2DM, have contraceptive needs outlined below with relative and absolute contraindications summarized in Table 4. For females with hyperandrogenic disorders, optimal androgen control is most important as outlined under the section for AUB. If contraception is required, women with CAH or PCOS may benefit from a COC containing an antiandrogenic progestin (e.g., drospirenone, cyproterone acetate, dienogest, chlormadinone acetate) [28, 64, 65]. Beyond differences in progestational activity and androgenicity, different generations of progestins show varying capacity for conversion into estrogen, and variable risk for VTE. Further information on this important area is referenced [66, 67].

Obesity (determined by a body mass index (BMI) >97th centile according to reference growth charts in children and adolescents (or >30 kg/m² in adults) is associated with cardiovascular risk factors, T2DM, and VTE. The risk for VTE in adults using COCs increases progressively with BMI [68], with age [69], and with progestin component [70]. In women with obesity and escalating risk factors (smoking, hypertension, dyslipidemia), the use of COCs is contraindicated and POPs, LARCs, or nonhormonal contraceptive options are indicated. For females with severe obesity (BMI >35 kg/m²) nonhormonal contraception or an IUD is indicated [60]. In general, the effectiveness of hormonal contraception is not affected by BMI according to a Cochrane Review published in 2016 [71].

Women aged less than 35 years with T1DM/T2DM without retinopathy, nephropathy, or neuropathy may use COCs. However, for females aged >35 years, or with additional cardiovascular risk factors such as hypertension or smoking, COCs should be avoided, and POPs, hormone-releasing IUD or non-hormonal contraception should be recommended instead [72]. In adolescents with severe disabilities with or without hypogonadism, unwanted exposure to sexual contact is not uncommon. Contraception may be requested by parents and/or carers. As discussed for AUB above, an individualized approach must be taken and the adolescent’s needs and expectations for sexual activities as well as her capacity to efficiently use any contraceptive method including hormones must be assessed [21]. The most effective and well-tolerated option is the progestin-bearing IUD [21, 38, 41].

In this mini-review, we have discussed pubertal induction and HRT, menstrual management, and contraception in girls and young women with complete gonadal insufficiency and women with partial or intermittent gonadal insufficiency due to common conditions affecting normal HPO-functioning. A professional relationship between physician, patient, and their family is paramount and will facilitate evolving management discussions regarding the underlying cause for gonadal insufficiency, preexisting risk factors such as a family history for VTE, individual needs (e.g., for menstrual control and/or contraception), and changing needs with maturation of the young woman. Complexity further increases when teams of specialists are involved such as in childhood cancer survivors after gonadotoxin exposure or fluctuating HPO-functioning due to relapses from chronic disease or in females with structural brain abnormalities and severe disability. Effective communication within the triangle of specialists, primary carers, and the family is required to manage such complex medical conditions and to support normal development, aiming for safety, efficacy, and best possible quality of life.

Figure 1 has been created with BioRender.com.

The authors have no conflicts of interest to declare.

No funding relevant to the conception, drafting and publication of this mini-review.

Flurina Saner, Christoph Saner, and Margaret Zacharin conceptualized the work. Hannah Ochsner, Gabby Atlas, Christa E. Flueck, and Anja Wueest provided contributions to the concept of the work. Hannah Ochsner, Flurina Saner, Christa E. Flueck, Margaret Zacharin, Gabby Atlas, Anja Wueest, and Christoph Saner provided important intellectual content, reviewed the work, and approved the final version for publication. Hannah Ochsner, Flurina Saner, Christa E. Flueck, Margaret Zacharin, Gabby Atlas, Anja Wueest, and Christoph Saner agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Hannah Ochsner and Flurina Annacarina Maria Saner contributed equally as first authors.Margaret Zacharin and Christoph Saner contributed equally as last authors.