Indications and efficacy of progestogen-monotherapy as menopause hormone therapy (MHT): A narrative review

Menopausal hormone therapy (MHT) remains the most effective treatment for vasomotor symptoms (VMS) and other manifestations of menopause; however, its use is limited in women with contraindications to estrogen. Progestogen monotherapy, though historically underutilized, represents a viable alternative in this population. This narrative review summarizes the indications, efficacy, and limitations of progestogen monotherapy as MHT. A structured literature search identified systematic reviews, guidelines, randomized controlled trials, and cohort studies evaluating progestogen monotherapy for menopausal symptom management, bone health, and oncologic safety. Evidence supports its use in patients with contraindications specific to estrogen, including those with certain gynecologic malignancies (e.g., low-grade endometrial stromal sarcoma, select ovarian cancers), prior venous thromboembolism, coronary artery disease, compensated liver disease, and endometriosis. Contraindications to progestogen monotherapy are limited to unexplained abnormal vaginal bleeding and personal history of breast cancer. Clinical data demonstrate that progestogens provide significant VMS relief, with efficacy observed across oral, intramuscular, and transdermal preparations. Micronized progesterone shows additional benefits for sleep quality, while synthetic progestins such as medroxyprogesterone acetate, megestrol acetate, and norethindrone acetate variably confer bone protection. Effects on mood appear neutral overall. Breast cancer risk associated with progestogen monotherapy remains uncertain due to limited and underpowered studies. Despite promising evidence, research is constrained by heterogeneous methodologies, small sample sizes, and lack of contemporary trials directly comparing progestogen monotherapy with standard MHT or nonhormonal alternatives. In conclusion, progestogen monotherapy is an effective, well-tolerated, and under-recognized therapeutic option for women with contraindications to estrogen-containing MHT. Its optimal use may be tailored to clinical context: micronized progesterone for sleep disturbance, norethindrone acetate for bone health, or progestins with known antineoplastic properties in hormone-sensitive tumors. Larger, high-quality studies are needed to better define long-term safety and efficacy. Title: Indications and efficacy of progestogen-monotherapy as menopause hormone therapy (MHT): A narrative review Running Title: Progestogen monotherapy in menopause Authors: Chloe Thomas* 1, Olivia Carere* 2, Lauren Clarfield 3, Michelle Jacobson 4 Affiliations: *Chloe Thomas and Olivia Carere share first authorship as they contributed equally to this work 1. School of Global Affairs, King’s College London, Strand, London, United Kingdom, WC2R 2LS 2. Temerty School of Medicine, University of Toronto, 1 Kings College Circle, Toronto, Ontario, Canada, M5S 1A8 3. Department of Obstetrics and Gynaecology, University of Toronto, 123 Edward Street Suite 1200, Toronto Ontario, Canada, M5G 1E2 4. Women’s College Hospital, Department of Gynecology, 76 Grenville St., Toronto, Ontario, M5S 1B2 Corresponding Author: Michelle Jacobson Address: 76 Grenville St., Toronto, Ontario, M5S 1B2 Phone: 4163237744 Email: [email protected] Contribution to Authorship: CT: research, methodology, manuscript writing and editing OC: research, methodology, manuscript writing and editing, table creation LC: research, methodology, manuscript writing and editing, table creation, supervision MJ: idea conception, methodology, manuscript editing, supervision

(up to 10): Progestins; Progesterone; medroxyprogesterone acetate; postmenopause; menopause; endometrial neoplasms; ovarian neoplasms

None Disclosure of Interests: Dr. Michelle Jacobson has received honoraria from the following organizations as well as serves as a member on the advisory boards listed below. Dr. Jacobson is also funded via the CIHR grant however, no such funding was directed at manuscript production. No other authors hold any conflicts of interest. Honoraria: ABBVIE, ASTELLAS, BAYER, DUCHESNAY, HOLOGIC, KYE, KNIGHT, LUPIN, SEARCHLIGHT, LILLY, SANOFI, PFIZER Advisory Boards: ABBVIE, ASTELLAS, BAYER, DUCHESNAY, ELSAI, HOLOGIC, IDORSIA, KYE, KNIGHT, LUPIN, SEARCHLIGHT, PFIZER Declaration of Funding Statement: No funding was received

Menopausal hormone therapy (MHT) remains the most effective treatment for vasomotor symptoms (VMS) and other manifestations of menopause; however, its use is limited in women with contraindications to estrogen. Progestogen monotherapy, though historically underutilized, represents a viable alternative in this population. This narrative review summarizes the indications, efficacy, and limitations of progestogen monotherapy as MHT. A structured literature search identified systematic reviews, guidelines, randomized controlled trials, and cohort studies evaluating progestogen monotherapy for menopausal symptom management, bone health, and oncologic safety. Evidence supports its use in patients with contraindications specific to estrogen, including those with certain gynecologic malignancies (e.g., low-grade endometrial stromal sarcoma, select ovarian cancers), prior venous thromboembolism, coronary artery disease, compensated liver disease, and endometriosis. Contraindications to progestogen monotherapy are limited to unexplained abnormal vaginal bleeding and personal history of breast cancer. Clinical data demonstrate that progestogens provide significant VMS relief, with efficacy observed across oral, intramuscular, and transdermal preparations. Micronized progesterone shows additional benefits for sleep quality, while synthetic progestins such as medroxyprogesterone acetate, megestrol acetate, and norethindrone acetate variably confer bone protection. Effects on mood appear neutral overall. Breast cancer risk associated with progestogen monotherapy remains uncertain due to limited and underpowered studies. Despite promising evidence, research is constrained by heterogeneous methodologies, small sample sizes, and lack of contemporary trials directly comparing progestogen monotherapy with standard MHT or nonhormonal alternatives. In conclusion, progestogen monotherapy is an effective, well-tolerated, and under-recognized therapeutic option for women with contraindications to estrogen-containing MHT. Its optimal use may be tailored to clinical context: micronized progesterone for sleep disturbance, norethindrone acetate for bone health, or progestins with known antineoplastic properties in hormone-sensitive tumors. Larger, high-quality studies are needed to better define long-term safety and efficacy. Key Clinical Points • Progestogen monotherapy is an under-recognized option for managing menopausal symptoms in women with contraindications to estrogen-containing MHT. • Indications include select gynecologic cancers (e.g., low-grade endometrial stromal sarcoma, certain ovarian tumors), history of thromboembolism, coronary artery disease, compensated liver disease, and endometriosis. • Contraindications are limited to unexplained abnormal vaginal bleeding and personal history of breast cancer. • Progestogens improve vasomotor symptoms; micronized progesterone also enhances sleep quality, while synthetic progestins such as norethindrone acetate may offer bone protection. • Mood effects appear largely neutral, though vigilance is needed in patients with pre-existing mood disorders. • Choice of agent should be individualized based on comorbidities and therapeutic goals (e.g., sleep, bone health, tumor-related considerations). Future Research • Large, contemporary randomized controlled trials directly comparing progestogen monotherapy with estrogen-containing MHT and non-hormonal options. • Long-term safety data on breast cancer recurrence risk and cardiovascular outcomes. • Mechanistic studies to clarify the role of progestogen receptor activity in bone health and vasomotor symptom relief. • Comparative effectiveness of oral, intramuscular, and transdermal routes of administration. • Exploration of precision medicine approaches to identify patient subgroups most likely to benefit from specific progestogen formulations.

Menopause represents an expected transitional life occurrence for biologic women at a median age of 51 years [1]. Clinically, menopause can be associated with significant bothersome symptoms including vasomotor symptoms (VMS), genitourinary symptoms of menopause, mood changes, sleep disturbance and changes in metabolism, among others [1]. First-line therapy for VMS for women without contraindications is menopausal hormone therapy (MHT), which traditionally includes estrogen and progestogen, when a uterus is present [1, 2]. While non-hormonal options exist for the treatment of VMS in patients with contraindications to MHT, this review intends to summarize the indications and efficacy of often over-looked progestogen monotherapy as MHT for individuals with contraindications to estrogen.

We searched PubMed from inception until August 2025 using key words and synonyms “progestogen”, “menopause”, “vasomotor symptoms” and “bone health”. We also reviewed relevant articles from the reference lists of selected articles. Selected articles included a combination of systematic reviews, practice guidelines, randomized controlled trials and cohort studies. This approach helps us answer the following questions: What are the indications for progestogen monotherapy? What are the contraindications to progestogen monotherapy? How effective is progestogen monotherapy for VMS? How effective is progestogen monotherapy for other symptoms of menopause? What is the impact of progestogen monotherapy on bone health? What are the indications for progestogen monotherapy? Progestogen monotherapy can be used for patients in whom the contraindication to MHT is specific to the estrogen component. Contraindications to progestogens include undiagnosed, abnormal vaginal bleeding and/or personal history of breast cancer, while contraindications to estrogen include these, as well as history of estrogen-dependent cancers, coronary heart disease, active or history of venous thromboembolism or stroke, known thrombophilias, active liver disease, and known or suspected pregnancy [1, 2]. In this review, we consider three groups who may benefit from progestin monotherapy: uterine neoplasms, ovarian neoplasms, and non-malignant contraindications to estrogen. Uterine Neoplasm Uterine neoplasms include both endometrial cancer (EC) and uterine sarcomas such as carcinosarcoma, leiomyosarcomas (LMS), adenosarcomas, and endometrial stromal sarcomas (ESS)[3]. The surgical treatment for most uterine cancers includes hysterectomy and bilateral salpingo-oophorectomy, which induces surgical menopause in premenopausal women [3]. Endometrial cancer is the most common gynecologic malignancy, with rising incidence among premenopausal women by 200% in the past three decades [3, 4]. EC is classified into type 1 tumors, which are estrogen-dependent, low-to-intermediate grade (grades 1 and 2), and typically express estrogen and progesterone receptors, and type 2 tumors, which are generally estrogen-independent, high grade, associated with endometrial atrophy, and frequently lack hormone receptor expression [3]. Guidelines from The Menopause Society (TMS) (formerly North American Menopause Society) advise against estrogen containing MHT in women with high grade or advanced stage EC [5]. Although type 2 ECs are not thought to be estrogen-driven, estrogen containing MHT is not advised due to the aggressive nature of these tumors and insufficient safety data, prompting a risk-averse approach. In these scenarios, progestogen monotherapy may be considered. While several systematic reviews and TMS support the use of estrogen containing MHT for surgically treated, stage 1, low grade, type 1 EC, progestogen monotherapy can be considered for highly risk averse individuals or those with other factors increasing risk of recurrence. The benefits of progestin monotherapy include some VMS relief, bone protection, as well as a chemotherapeutic approach for ER+ tumours, where progestogen therapy can be used to treat ER+ EC in certain circumstance [5, 6]. MHT is contraindicated in certain uterine sarcomas due to the hormone-dependent nature of the tumour. Estrogen-containing MHT can be considered for some subtypes such as adenosarcoma and carcinosarcoma [7, 8]. In contrast, endometrial stromal sarcoma (ESS) and leiomyosarcoma (LMS) often exhibit hormone sensitivity. One of the chemotherapeutic approaches for low grade ESS includes progestogen therapy, thus progestogen monotherapy for menopause management can be considered for these tumours. In contrast, progestogen monotherapy is not recommended in LMS and in high-grade ESS, given the absence of sufficient evidence regarding safety and efficacy [8]. Ovarian Neoplasm Ovarian cancer (OC) is a heterogeneous disease, comprised of epithelial ovarian cancer subtypes (serous tumours, mucinous tumours, endometrioid tumours, and clear cell tumours), germ cell tumours (dysgerminoma, embryonal cell, yolk sac tumour, choriocarcinoma, immature teratoma), and sex cord stromal tumors (granulosa cell tumour, sertoli-leydig tumour) [9]. The current consensus in medical literature concludes that MHT can be safely considered in patients with most epithelial ovarian cancers, except for low-grade serous carcinoma or higher grade, later stage endometrioid ovarian cancer - where caution is advised due to risk of recurrence and malignant transformation of endometriotic implants [7, 8, 10-16]. In contrast, granulosa-cell tumours, are known to be estrogen sensitive and estrogen-containing MHT may stimulate microscopic residual disease leading to recurrence [17]. Progestogen monotherapy offers an alternative for symptom management in OC survivors requiring or who prefer non-estrogen treatment for MHT, particularly in endometroid and granulosa cell tumours. Non-Malignant Indications Progestogens are not contraindicated for individuals with coronary artery disease, and any progestogen monotherapy can be used to treat symptoms of menopause in this population. While estrogen containing MHT is not absolutely contraindicated for individuals with advanced, or deeply infiltrating endometriosis, several systematic reviews propose an increased risk of recurrence or malignant transformation of endometriosis with estrogen [18, 19]. As such, progestogen monotherapy can be used in this population if shared decision making precludes estrogen containing therapy. In patients with compensated liver dysfunction, progestogen monotherapy remains acceptable, though caution is warranted in decompensated cirrhosis [20]. Currently, no studies specifically evaluate the risk of venous thromboembolism (VTE) associated with progestogen monotherapy for hormone replacement therapy in postmenopausal patients, and VTE is not regarded as a contraindication to progestogen use in this population. However, evidence from large observational studies and meta-analyses indicates that certain synthetic progestins, including depot or oral medroxyprogesterone acetate, megestrol acetate, and norpregnane derivatives, are associated with an increased risk of VTE [21-24]. In contrast, this risk has not been observed with micronized progesterone. Accordingly, progestogen monotherapy may be considered an appropriate therapeutic option for postmenopausal patients in whom estrogen-containing MHT is contraindicated due to prior or active VTE, with a preference for micronized progesterone. What are the contraindications to progestogen therapy? The only two contraindications to progestogens per the Society of Obstetricians and Gynecologists of Canada guideline are undiagnosed abnormal vaginal bleeding and personal history of breast cancer [2]. The relationship between progestogen and breast cancer risk is best elucidated by two large observational studies, the Women’s Health Initiative and the Million Women Study, which both demonstrated an increased risk of breast cancer when patients were given combined MHT compared to estrogen-alone therapy [25, 26]. In contrast, systematic reviews have noted that most studies of progestogen-only regimens do not show increase in breast cancer risk, but these findings are limited by small sample sizes and short follow up periods, making definitive conclusions difficult [27]. Women exposed to MHT after breast cancer have shown an increased risk of recurrence in two Swedish RCTs, but the risk of progestogen monotherapy has not been described [28, 29]. How effective is progestogen monotherapy for VMS? While estrogen is traditionally regarded as the main driver of VMS relief in MHT, evidence demonstrating greater improvements in VMS among patients using combined therapy compared to estrogen alone supports an independent beneficial effect of progestogens [30]. Therefore, individuals with contraindications to estrogen may experience improvement in VMS from progestogen monotherapy. Progestogen monotherapy can be oral, injectable or transdermal. We identified 15 studies evaluating the efficacy of progestogen monotherapy versus placebo on VMS, including 8, 4 and 3 studies evaluating oral, injection and topical progestogens respectively (Table 1) [31-44] Oral Progestogen Table 1 summarizes the characteristics and findings of studies evaluating the effectiveness of oral progestogen as a monotherapy treatment for VMS. Oral Micronized Progesterone Two randomized control trials investigated micronized progesterone versus placebo for VMS. Hitchcock et al. (2012) randomized 133 biologically female patients (aged 44 to 62 , 1-10 years since final menstruation) with moderate to severe VMS to receive either 300 mg nightly of oral micronized progesterone or placebo capsules over 12 weeks [32]. The primary outcome was a change in VMS score over the final 28 days, using the Daily Menopause Diary collected starting 4 weeks prior to the intervention. Progesterone provided greater benefit in VMS score, VMS frequency, and VMS severity compared to placebo, but only achieved statistically significant advantage for VMS score (mean adjusted difference: −4.3 95% CI −6.6 to −1.9, P<0.05). Sub-group analysis of women with more frequent-severe symptoms showed significant benefit in VMS score and frequency, but not severity. Daytime sub-group analysis showed improvement in daytime VMS score, frequency and severity, demonstrating benefit of the progesterone not solely due to improved sleep masking night sweats. Prior et al. (2023) conducted a double blinded clinical trial, randomizing 189 patients aged 35-58 in perimenopause with bothersome night sweats and/or hot flashes to receive either 300 mg oral micronized progesterone or placebo capsules for 3 months after 1 month of untreated baseline [34]. The primary outcome was the change in daily VMS score. They found no statistically significant difference in VMS score between groups (RR 0.79 95% CI 0.54 to 1.15, Rate Difference -1.51 95% CI − 3.97 to 0.95, P =0.222). However, the 95% CI included values (lower bound -3.97) that could represent a minimal clinically important difference (defined as -3), indicating that the study’s sample size was underpowered to exclude a clinically meaningful benefit. Patients randomized to progesterone perceived significant improvement in overall night sweats ( P =0.023), night sweat frequency ( p =0.015), night sweat intensity (P<0.001), daytime VMS intensity ( P <0.014), sleep quality (P=0.005), and reduced perimenopause-related life interference (P=0.017) [34]. Oral medroxyprogesterone acetate There are three randomized control studies evaluating oral medroxyprogesterone (MPA) versus placebo for VMS. Schiff et al. (1980) conducted a double-blind crossover study in 32 postmenopausal women experiencing vasomotor flushes (aged 45-67), comparing oral MPA 20 mg daily to placebo, each administered for 12 weeks [35]. Among patients assigned first to placebo, weekly hot flushes decreased by 25.9% by weeks 9-12 with placebo and further by 34.5% after crossing over to MPA (P<0.05). Patients initially assigned to MPA experienced a 73.9% reduction in the number of weekly hot flushes by weeks 9-12 (P<0.05), but experienced a marked increase in hot flushes, approaching baseline levels, when switched to placebo [35]. Aslaksen et al. (1982) performed a double-blind cross-over trial in 24 patients with recently treated stage 1 endometrial carcinoma experiencing VMS [31]. Participants were randomized to receive oral MPA 100mg BID (200 mg/day) or placebo for 12 weeks, followed by 1 week where both groups took no medication, and then crossed over to the alternate treatment for another 12 weeks. They found a significantly greater proportion of patients free of hot flushes during MPA treatment compared to placebo (81% MPA and 15% placebo, P<0.001) and significantly greater proportion of patients who were free of sweating (72% MPA and 6% placebo, P<0.01). No serious adverse events were reported in the MPA group despite the high dose. Though retention was high, side effects included weight gain (mean weight gain 1.25 kg vs. 0.14 kg placebo, p160 mmHg in n=5 MPA vs. n=2 placebo, rise in diastolic >90 mmHg in n=3 MPA vs. n=1 placebo) [31]. Prior et al. (1994) conducted a double-blind crossover trial in 14 postmenopausal patients (ages 43-63) not currently on hormone therapy. Participants received 10 days/month of oral cyclic MPA 10 mg daily and identical placebo given during 2 consecutive months in random order [33]. Each woman completed a daily menopause diary rating symptoms on a 0–4 scale, capturing breast tenderness, fluid retention, anger, depression, anxiousness, self-worth, energy, headache, vaginal dryness, constipation, and outside stresses. A composite score evaluating “PMS-like symptoms” did not differ between the medroxyprogesterone and placebo treatments (median 26 vs 25; P=.0.82) [33]. Oral Megestrol Acetate There are three available papers evaluating the effect of megestrol acetate (MA) on VMS. Erlik et al. (1981) conducted a prospective, dose-ranging study in 10 postmenopausal women experiencing hot flashes. The study evaluated the frequency of hot flashes during periods of no treatment and during 4 week treatment intervals with oral MA 20 mg, 40 mg, and 80 mg daily [37]. A significant reduction in the frequency of flushing episodes was observed at all dose levels of MA compared to baseline (P<0.01). The effect was dose-dependent, with significantly fewer subjective flushes at 40 mg and 80 mg vs. 20 mg (P<0.01). Reported side effects including breast tenderness (n=1) and mild weight gain (n=1). No adverse effects or cases of abnormal vaginal bleeding, mood changes, or blood pressure changes were observed [37]. Loprinzi et al. (1994) conducted a randomized, double-blind, cross-over trial in 100 women with a history of breast cancer experiencing significant vasomotor symptoms, and 66 men who had undergone surgical bilateral orchiectomy[45]. Results were described separately, and this paper will only comment on results for biologically female participants. Approximately 80% of women were taking tamoxifen at study entry. Participants were randomized to receive either oral MA 20 mg BID or placebo for 4 weeks, followed by a 1-week washout and then crossed to the alternate treatment for another 4 weeks. After the ninth week, participants continued to take MA if they desired with titration from 10 to 80 mg of MA as needed to determine the lowest dose which effectively controlled hot flashes. The primary outcome was the frequency and severity of hot flashes, recorded daily by participants. Results showed a significant reduction in the frequency of hot flashes (26% on MA vs. 73% on placebo, P<0.001) and in the hot flash score (17 on MA and 73 on placebo, P<0.001). The study group also noted a reproducible spike in the severity of hot flashes for patients on tamoxifen only in the first several days of taking MA. Patients were asked which treatment period they felt was more effective and among those who received placebo first, 87% preferred MA, while among those who received MA first, 45% preferred MA and 40% preferred placebo, likely reflecting a prolonged carryover effect of MA. There was no difference in side effects on weekly questionnaire in the MA and placebo group [45]. Goodwin et al. (2008) conducted a phase III randomized placebo-controlled trial in 286 patients with T1-3, N0-1, M0 breast cancer and significant VMS [38]. The majority (85%) of participants were taking tamoxifen at study entry. Participants were randomized to placebo (n=102), oral MA 20 mg daily (n=93), or oral MA 40 mg daily (n=93) for three months. The primary outcome was the proportion of patients with ≥75% reduction in hot flashes from baseline. This was achieved by 14% on placebo, 65% on 20 mg MA and 48% on 40 mg MA (P<0.0001 for both MA arms vs. placebo). There was no significant benefit between the 20 mg and 40 mg dose. Among patients who achieved the primary endpoint at 3 months, the majority maintained this response at 6 months (77% on 20 mg and 81% on 40 mg). Adverse events included edema and weight gain (placebo group), fatigue (20 mg MA group), and depression, fatigue, nausea and weight gain (40 mg MA group) [38]. It is important to note that both trials by Goodwin et al. (2008) and Loprinzi et al. (1994)enrolled breast cancer survivors, a population in whom progestogen therapy is generally contraindicated [38, 45]. However, Goodwin et al. (2008) specifically designed their trial to evaluate megestrol acetate as an alternative strategy for tamoxifen-treated breast cancer survivors with severe vasomotor symptoms, given the limited efficacy of nonhormonal therapies at the time and the absence of data on progestogen monotherapy in this population) [38]. Oral Norethindrone Acetate (NETA) Norethindrone acetate (NETA) or norethindrone (NET) are oral progestogens which can be considered as a progestogen monotherapy. While no studies evaluate the efficacy of NETA or NET for VMS in a post-menopausal population, NETA (5mg PO daily) is commonly used as an effective monotherapy for add-back hormone therapy in iatrogenic menopause secondary to GnRH agonists and antagonists to relieve bothersome symptoms of menopause [46]. The chemical structure of NETA is distinct from other progestogens, specifically regarding its estrogen receptor tissue effect [47]. In the liver, NET aromatized and conjugated into ethinyl estradiol at a rate of approximately 6 µg per milligram of NETA, making a 5 mg dose of NETA roughly equivalent to an oral dose of 20–30 µg of ethinyl estradiol [47]. Regardless of some estrogen receptor activity, NETA is strongly antagonistic on the endometrium thereby protecting individuals on NETA alone from endometrial cancer. Given its partial conversion to ethinyl estradiol, NETA should primarily be considered in cases where the contraindication to estrogen is limited to the endometrium, as it remains strongly antagonistic at the endometrial level despite systemic estrogenic activity. Intramuscular Progestin Four studies evaluate the effects of intramuscular progestin treatment at reducing VMS in postmenopausal women (Table 2). Bullock et al. (1975) conducted a double-blind study in which 69 patients were randomized to either receive injectable DMPA 150 mg IM monthly (n=57) or a 1.5ml sterile saline placebo (n=12) [36]. Patients were observed and evaluated for changes in severity and frequency of hot flashes, recorded using weekly symptom diary. At six months, 89.5% (n=51) of patients receiving DMPA reported a significant reduction in hot flashes, compared to only 25% of the placebo group (n=3) (P<0.0001). Abnormal uterine bleeding was the most common, occurring in 18 patients (43%) on DMPA vs. 2 (20%) on placebo [36]. Morrison et al. (1980) conducted a double-blind, placebo-controlled study where 48 women were randomized to receive either 50, 100, or 150 mg of Depo-Provera (DMPA) or placebo, respectively [40]. The primary outcome was reduction of hot flash frequency and intensity. Significant statistical differences in discontinuation rates were observed amongst groups with 75% (n = 9) of the placebo group dropping out of the study compared to only 5.6% (n = 2) of patients in the treatments groups (P < 0.0002). In terms of subjective improvement of VMS, the placebo group reported a perceived 15- 20% improvement throughout the course of therapy whereas the treatment group reported a 75-100% improvement. Hot flash frequency was reduced by 25 to 45% in DMPA groups with placebo groups exhibiting little to no reduction (P < 0.0001). There was no statistically significant dose-dependent relationship amongst the different treatment groups, however patients receiving either 100 mg or 150 mg of DMPA reported higher patient satisfaction with treatment. Symptoms of depression and emotional lability that were initially reported mostly resolved throughout the course of treatment. No statistically significant side effects were observed [40]. Bertelli et al. (2002) conducted a randomized trial in 71 postmenopausal women (aged 40-72) with a history of breast cancer, comparing 500 mg of IM depot medroxyprogesterone acetate (DMPA) serial injections to 40 mg of oral MA daily [41]. Eighty-five percent of participants were taking tamoxifen at study entry. The primary outcome was relief of hot flashes by \(\geq\) 50% based on data from a symptom diary. Seventy-five percent of patients receiving DMPA reported a significant reduction in hot flashes as well as 67% of patients receiving MA. There were no statistically significant differences between each treatment group in terms of VMS-reduction during the study (P=0.5). However, maintenance of response at 24 weeks after discontinuation of therapy was significantly higher in the DMPA group (89%) compared to the MA group (45%) (P=0.03). Loprinzi et al. (2006) conducted a randomized trial in 227 women with bothersome hot flashes, assigning them to receive either a single-dose IM injection of 400 mg MPA, three doses of 500 mg MPA injected IM every 2 weeks, or 37.5 mg of venlafaxine daily for 1 week followed by 75 mg per day for the remainder of the study [39]. The three-dose MPA arm was discontinued after only nine patients were accrued. The primary outcome was a reduction in hot flash frequency and severity, measured via a daily hot flash questionnaire and a weekly symptom diary. Patients satisfied with treatment after 6 weeks continued under observation for the following 11 months. With 118 total patients eligible for analysis, after 6 weeks, 79% of patients receiving single-dose IM MPA reported a mean reduction in hot flashes compared to 55% in the venlafaxine arm (P\(\leq\)0.0001). Side effects were not significantly different between groups and mostly focused on known side effects of venlafaxine rather than MPA [39]. Transdermal Progestogens Three double-blind placebo-controlled studies evaluate the effect of transdermal progestogens on VMS (Table 3). Leonetti et al. (1999) conducted a double-blinded trial randomizing 102 women within 5 years of menopause, free of MHT for minimum 1 year, to receive either 20 mg of transdermal progesterone mixed with tocopherol cream or tocopherol cream alone applied daily for 12 months [43]. The primary outcome was control of VMS, documented via a weekly symptom diary. Among those with baseline VMS, improvement or resolution occurred in 83% in the progesterone group compared to 19% receiving placebo (P<0.001). Most women experienced maximum relief after 1 month. Twelve patients (11.8%) withdrew due to rashes (n=2), unrelated hospitalizations (n=2), poor compliance (n=4), or medication nonadherence (n=4) [43]. Wren et al. (2003) conducted a double-blind randomized control trial involving 80 women who were at least 6 months postmenopausal, had stopped hormone therapy for ≥8 weeks, and experienced at least one hot flush daily. Participants were randomized to receive 32 mg of transdermal progesterone cream or a placebo cream applied daily for 12 weeks [44]. The primary outcome was a change in VMS, assessed by daily symptom diaries. After 12 weeks, there were no statistically significant difference in VMS between progesterone and placebo groups (median change -1.0 vs 0.0, P=0.07), nor were there significant differences in somatic, anxiety, depression, or sexual response domains [44]. Benster et al. (2009) conducted a double-blind, randomized study in 230 post-menopausal women aged 40-60 years with moderate to severe menopausal symptoms. Participants were randomized to receive progesterone cream at doses of 5 mg (0.75%), 20 mg (3%), 40 mg (6%), or 60 mg (9%) daily, or a placebo cream, applied to the forearm for 24 weeks [42]. The primary outcome was change in the psychological, somatic, and vasomotor components of the Greene Climacteric Scale. Study results show that VMS were reduced at 6 months, but data were not statistically significant when compared to the placebo group ( P = 0.22, 0.23, 0.06, 0.23 respectively for 5 mg, 20 mg, 40 mg, 60 mg). Although not statistically significant, there appeared to be a dose-response, with less weekly hot flushes with higher doses [42]. How effective is progestin monotherapy for other symptoms of menopause? Sleep Disturbed sleep is a significant concern for postmenopausal individuals, adversely impacting quality of life and contributing to long-term cardiovascular, metabolic, and cognitive morbidity. While improvement in night sweats with MHT often confounds the assessment of direct sleep effects of therapies, a large systematic review found that micronized progesterone containing MHT improved sleep disturbance compared to estrogen alone, suggesting a role of at least micronized progesterone to improve sleep [48]. Micronized progesterone is known to have sedative-like properties and is recommended to be administered at bedtime to minimize daytime drowsiness and optimize tolerability. Consistent with this, the two randomized trials evaluating micronized progesterone for vasomotor symptoms reported statistically significant improvements in self-perceived sleep quality compared to placebo [32, 34]. Meta-analytic evidence further supports these findings, demonstrating reduced sleep latency and improved self-reported sleep quality with micronized progesterone, though effects on total sleep time and sleep efficiency remain inconsistent [49-51]. In contrast, synthetic progestogens such as medroxyprogesterone acetate (MPA) and megestrol acetate (MA) appear to confer minimal or inconsistent sleep benefits[48, 50]. For example, Bullock et al. (1975) described above, found no statistically significant reduction in self-reported insomnia among individuals randomized to MPA (P=0.2) [36]. This data suggests that micronized progesterone monotherapy is likely to improve sleep in postmenopausal patients, whereas synthetic progestogens do not. Mood New or worsening depression and anxiety are well documented symptoms of menopause, with highest risk for patients with a history of depression [5]. While progestogens have been linked historically with worsening of mood symptoms in pre and post-menopausal patients[5, 52], a recent systematic review and meta-analysis of randomized trials in postmenopausal women found that the addition of progestogens to estrogen therapy neither worsened nor significantly improved depressive symptoms compared to estrogen alone or placebo, regardless of dose or route of progestogen used [53]. Hormone therapy with unopposed estrogen shows some efficacy for management of depressive symptoms in menopause, especially in perimenopause [5, 54] but no studies directly evaluate the role of progestogen-monotherapy as a treatment for peri- or post-menopausal mood symptoms. Nonetheless, several of the trials reviewed in the VMS efficacy section also examined mood-related outcomes—including depression, anxiety, and psychological well-being—as secondary endpoints. Across these studies, progestogen monotherapy had no significant negative impact on mood, regardless of dose or administration route – suggesting at least a neutral effect [32, 34, 36, 38, 42-44]. While caution is warranted given pre-established relationships between certain progestogens and low mood especially for patients with pre-existing mood disorders [55, 56], the studies reviewed showed no clear deleterious mood effects using progestogen monotherapy [5]. What is the impact of progestogen monotherapy on bone health? Bone loss and increased fracture risk in menopause is a major cause of morbidity and mortality in post-menopausal women [5, 57]. Though estrogen has been identified as the dominant mediator in bone health for women, bone metabolism is governed by a complex interplay of hormonal factors and the role of progestogen monotherapy remains uncertain but may exert neutral, protective or harmful effects [58]. Moreover, oral synthetic progestins such as MPA and MA, have distinct chemical structures with heterogenous and dose dependent receptor activity contributing to mixed conclusions. A meta-analysis published in 2017 of 1000 menopausal patients revealed significantly improved BMD on CEE plus MPA compared with CEE alone, implying some protective role of MPA, at least when given with estrogen [59]. This protective benefit of MPA and MA (both with known glucocorticoid and androgen receptor activity) has been shown non-reproducibly when given without combined estrogen [37, 60, 61]. Depot MPA has traditionally been associated with reversible bone mineral density loss in pre-menopausal patients [62]. However, this is proposed to be secondary to hypo-estrogen effects based on the effects of DMPA on the hypothalamic-pituitary-ovarian axis and therefore do not apply in the same way to this post-menopausal population who are already estrogen deplete. In addition, in a two-year randomized control trial, Liu and Muse (2005) identified norethindrone acetate (NETA) as the only progestogen-only regimen to prevent BMD loss compared to micronized progesterone and MPA[57]. These findings are supported by studies in premenopausal women with leuprolide-induced hypoestrogenism, where norethindrone acetate (NETA) also preserved BMD [46, 63]. Other progestogens, such as micronized progesterone and transdermal progestins have not been shown to be as consistently or at all protective for bone [43, 58]. In summary, certain progestogen monotherapies, namely MPA, MA and NETA, have been shown to unreliably but significantly exert some protective effect on bone health. Regardless, even for patients eligible for HRT, non-estrogen medications are preferred for treatment of existing osteoporosis [58]

This narrative review identifies progestogen monotherapy as a valuable and under-recognized option for the management of menopausal symptoms in patients for whom estrogen-containing therapies are contraindicated. Progestin monotherapy is clinically indicated in a variety of scenarios where estrogen in MHT is contraindicated. Specifically, we propose consideration in patients with certain uterine or ovarian cancers, deep infiltrating endometriosis, active or previous thromboembolism, known thrombophilias, limited liver disease, and coronary heart disease. Its use can be especially optimized where progestins could be used as a medical therapy, such as in estrogen-dependent cancers. As reviewed, progestogens can be delivered orally (micronized progesterone, MA, MPA or NETA), intramuscularly (DMPA) or transdermally. NETA, as outlined in the main text, undergoes hepatic conversion to low levels of ethinyl estradiol but remains strongly antagonistic at the endometrium. Accordingly, its use in monotherapy is best suited to patients whose contraindication to estrogen is related to its effect on the endometrium such as endometrial neoplasm or endometriosis. This review is limited by the substantial heterogeneity among included studies, particularly in methodologies, outcome measures, and sample sizes. Many studies evaluating progestogen monotherapy were conducted decades ago, with small cohorts insufficiently powered to exclude clinically meaningful differences. Additionally, inconsistency in intervention protocols, regarding dose, route, and agent, limits direct comparability and further underscores the need for contemporary, large-scale randomized trials to more definitively establish progestogen monotherapy’s safety and efficacy. In summary, progestogen monotherapy is an effective, often under-used option for patients with contraindications to estrogen containing MHT. This may be particularly helpful in young patients who would benefit from bone protection from NETA or synthetic progestins or in patients with significant sleep concerns who would benefit from micronized progesterone. This therapy is well-tolerated and represents a safe alternative to non-hormonal options available for VMS.

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Authors Metrics & Citations Metrics Article Usage 876views 254downloads Citations Download citation Chloe Thomas, Olivia Carere, Lauren Clarfield, et al. Indications and efficacy of progestogen-monotherapy as menopause hormone therapy (MHT): A narrative review. Authorea. 04 September 2025. DOI: https://doi.org/10.22541/au.175697697.74288051/v1 DOI: https://doi.org/10.22541/au.175697697.74288051/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.