How Does Vyleesi Feel? What Women Report Before, During, and After Each Dose

What Is HSDD and Who Gets Diagnosed With It?

Hypoactive sexual desire disorder (HSDD) is a formal psychiatric and medical diagnosis describing persistently low or absent sexual desire that causes personal distress. The DSM-5 merged it into Female Sexual Interest/Arousal Disorder (FSIAD), but the FDA retained the HSDD label for drug-approval purposes. Prevalence estimates in the United States put HSDD at roughly 8 to 10 percent of adult women when the distress criterion is included, with higher rates among surgically menopausal women [1].

The diagnosis is clinical. No single lab value confirms it. A 2014 review in the Journal of Sexual Medicine noted that "absent spontaneous desire alone is insufficient for diagnosis; the clinician must also document personal distress or interpersonal difficulty" [2]. That framing matters because many women with low testosterone or low estrogen report diminished desire but do not meet the distress threshold, which changes whether drug therapy is appropriate.

HSDD has two FDA-cleared pharmacologic treatments: flibanserin (Addyi), a daily oral serotonin 1A agonist and 2A antagonist approved in 2015, and bremelanotide (Vyleesi), an as-needed melanocortin agonist approved in August 2019 [3]. Both are indicated only for premenopausal women in their current labeling, although off-label use in postmenopausal women does occur under physician discretion.

How Vyleesi Works in the Body

Bremelanotide activates melanocortin receptors (primarily MC3R and MC4R) in the central nervous system, particularly in areas governing dopaminergic reward pathways. Think of it as activating the brain's motivational circuitry rather than raising a specific hormone level. This mechanism is entirely distinct from estrogen, progesterone, or testosterone, which means it can be used alongside hormone therapy without pharmacokinetic interference [4].

The drug is delivered via a single-use autoinjector to the abdomen or thigh. Bioavailability by the subcutaneous route is roughly 100 percent, and peak plasma concentration occurs at about 1 hour post-injection. The terminal half-life is approximately 2.7 hours, which explains why effects are transient and why blood pressure returns to baseline within 12 hours in most women [5].

Receptor activation at MC1R in melanocytes also causes transient skin and facial hyperpigmentation with repeated use. In RECONNECT, 1 percent of participants developed focal hyperpigmentation of the face, breasts, or gums that persisted beyond the trial period, prompting the FDA to add a warning for women with darker skin tones or those with a history of melasma [3].

What the Physical Sensation Actually Feels Like

Most women describe the first 45 to 90 minutes after injection in terms of three distinct sensations.

Flushing. A warm, spreading flush across the face, neck, and sometimes chest is the most consistently reported sensation. In RECONNECT phase 3 (N=1,267 women across two parallel trials), flushing occurred in approximately 20 percent of bremelanotide recipients compared with 3 percent of placebo recipients [5]. The flush is not the same as a hot flash. Women who have experienced menopausal hot flashes describe the Vyleesi flush as shorter and less intense, usually resolving within 30 to 45 minutes.

Nausea. This is the side effect most likely to affect adherence. Nausea affected roughly 40 percent of women on bremelanotide in RECONNECT versus 1 percent on placebo [5]. Severity is usually mild to moderate. Taking an over-the-counter antiemetic (ondansetron 4 mg orally) 30 minutes before injection was permitted in open-label extension studies and reduced nausea meaningfully in most cases. Women who experience severe vomiting are advised to stop using the drug.

Mild fatigue or sedation. A subset of women reports a brief 30 to 60 minute period of low energy following the flush. This is consistent with MC4R activation affecting orexin signaling. It generally resolves before the anticipated sexual activity window.

A key point: Vyleesi does not create arousal in the absence of a partner or sexual context. Women consistently describe it as removing a "friction" or "block" rather than generating desire independently. That nuance matters clinically.

The HealthRX clinical team uses a three-axis framework when counseling women about expected Vyleesi experience:

1. Physical tolerance axis. Can the patient tolerate transient nausea and flushing? Women with a history of motion sickness or migraine-associated nausea report higher baseline nausea sensitivity and may benefit from scheduled antiemetic pretreatment.
2. Desire-vs.-arousal axis. Vyleesi addresses desire (motivation to engage). Women whose primary complaint is physical arousal difficulty or pain with intercourse need concurrent evaluation for genitourinary syndrome of menopause (GSM), inadequate lubrication, or pelvic-floor dysfunction.
3. Hormonal status axis. Women with concurrent untreated hypoestrogenism or low testosterone may see partial response to Vyleesi alone. Addressing underlying hormonal deficiency alongside bremelanotide often produces better reported outcomes.

Is Low Libido in Women Hormonal?

Low libido in women has a hormonal component in a significant percentage of cases, but the relationship is not simple or linear. Three hormones most directly affect female sexual desire: estrogen, progesterone, and testosterone.

Estrogen maintains the integrity of vaginal tissue and supports lubrication, making intercourse comfortable enough to want in the first place. The 2023 Menopause Society (formerly NAMS) position statement notes that "genitourinary syndrome of menopause, driven by declining estrogen, is present in up to 27 to 84 percent of postmenopausal women and frequently co-occurs with low desire" [6]. Painful sex because of atrophic tissue depresses desire secondarily, even when the primary desire circuitry is intact.

Testosterone in women is produced by the ovaries and adrenal glands at roughly 5 to 10 percent of male levels but acts on the same androgen receptors that influence mood, energy, and libido. Serum testosterone declines progressively from the mid-twenties onward, with the steepest drop occurring after surgical oophorectomy. A 2019 systematic review in The Lancet Diabetes and Endocrinology (N=8,480 women across 36 trials) found that testosterone therapy improved sexual function scores, including desire, significantly more than placebo or comparator, with a standardized mean difference of 1.16 for the desire domain of the Female Sexual Function Index (FSFI) [7].

Progesterone's role is more ambiguous. Synthetic progestins (particularly medroxyprogesterone acetate) may blunt libido, whereas micronized progesterone has a more neutral or slightly anxiolytic effect that some women associate with improved desire indirectly through reduced anxiety [8].

Cortisol and thyroid hormones also contribute. Chronic cortisol elevation suppresses hypothalamic GnRH pulsatility, reducing downstream LH and thereby lowering ovarian testosterone output. Hypothyroidism blunts dopamine signaling, mimicking the flat affect that accompanies low desire. Any workup for HSDD should include TSH and free T4 alongside sex hormones.

Does HRT Increase Libido?

Hormone replacement therapy (HRT) can improve libido in women, but the effect depends heavily on the specific hormones used, the route of delivery, and the underlying hormonal deficit.

For perimenopausal and postmenopausal women whose low desire tracks with estrogen decline, systemic estradiol (oral, transdermal patch, or gel) reduces GSM symptoms, restores vaginal tissue, and removes the pain-related brake on desire. The SWAN study followed 3,302 women longitudinally and found that moderate-to-severe sexual dysfunction was 1.5 times more likely in women with low estradiol after adjusting for age and mental health factors [9].

Estrogen alone does not reliably restore desire in women who also have low testosterone. Oral estrogen additionally increases sex hormone-binding globulin (SHBG), which binds free testosterone and can paradoxically worsen androgen insufficiency. Transdermal estradiol avoids the first-pass hepatic effect and produces a smaller SHBG rise, making it the preferred route when testosterone add-back is being considered [7].

Combined HRT (estrogen plus progesterone) in women with an intact uterus shows variable libido effects depending on the progestogen. A 2008 randomized trial in Menopause found that women receiving transdermal estradiol plus oral micronized progesterone reported higher FSFI scores than those on conjugated equine estrogens plus medroxyprogesterone acetate at 12 months [8].

Can Testosterone Help Women's Libido?

Testosterone is the most evidence-backed pharmacological option for low libido in women, despite lacking an FDA-approved product for this indication in the United States as of 2025. Physicians prescribe it off-label as compounded topical gels or creams, typically at doses of 0.5 to 2 mg per day of testosterone applied transdermally.

The 2019 Lancet meta-analysis referenced above provides the clearest summary: testosterone therapy significantly improved the desire domain of the FSFI, along with arousal, lubrication, orgasm frequency, and satisfaction [7]. The International Society for the Study of Women's Sexual Health (ISSWSH) published a process-of-care algorithm in 2020 recommending that clinicians "consider a trial of testosterone in women with HSDD after ruling out other contributing factors, using the lowest effective dose with regular monitoring" [10].

Safety data at physiologic female doses (targeting serum total testosterone of 30 to 60 ng/dL) show no significant cardiovascular signal over 24-month periods in available trial data. Supraphysiologic dosing, however, carries risks of acne, hirsutism, clitoral enlargement, and voice changes. Monitoring with a serum testosterone level at 3 to 6 weeks after initiation and again at 3 months is standard practice per ISSWSH guidelines [10].

Testosterone does not replace the role of estrogen in women with GSM. The two work on different tissues and different pathways. A woman using testosterone cream for desire while also experiencing vaginal dryness and painful intercourse needs both interventions addressed.

Vyleesi vs. Hormonal Options: Choosing the Right Approach

Selecting between Vyleesi, HRT, and testosterone depends on menopausal status, hormonal lab findings, contraindications, and patient preference around delivery method.

Premenopausal women with HSDD and normal hormone levels. Vyleesi or Addyi are the two FDA-approved choices. Testosterone is off-label but may be trialed after a full hormonal workup confirms no deficiency requiring direct replacement.

Perimenopausal or postmenopausal women with low estradiol and low desire. Systemic HRT (transdermal estradiol plus micronized progesterone if uterus is present) should be the first hormonal intervention. Adding testosterone if desire remains low after 3 to 6 months of stable HRT is a reasonable clinical step, per ISSWSH 2020 guidelines [10].

Women with contraindications to estrogen (e.g., hormone-receptor-positive breast cancer history) who have HSDD. Testosterone at physiologic doses may be an option in consultation with the treating oncologist. Vyleesi has no hormonal mechanism and carries no estrogen-related theoretical cancer risk, making it a candidate for discussion in this population, though no dedicated safety trial exists in hormone-sensitive cancer survivors [3].

Systemic cardiovascular disease or uncontrolled hypertension. Vyleesi is contraindicated. The mean +6 mmHg systolic rise documented in RECONNECT could be clinically relevant in a woman already at elevated cardiovascular risk [5].

Practical Dosing and Timing for Vyleesi

The approved dose is 1.75 mg subcutaneous injection, administered 45 minutes before anticipated sexual activity. The injection can go into the abdomen or thigh. Women should not inject into the upper arm due to pharmacokinetic variability in that site per the prescribing information [3].

No more than one dose per 24-hour period. There is no benefit established for dosing more frequently, and the transient hypertension concern accumulates. Women should not take Vyleesi every day as a standing dose; it is strictly on-demand.

If nausea is dose-limiting, ondansetron 4 mg taken orally 30 to 60 minutes before the injection reduces nausea severity in most women without altering bremelanotide pharmacokinetics. This pretreatment is not listed in the official label but is widely used in clinical practice and was evaluated in the open-label extension of RECONNECT [5].

Women using naltrexone for any indication should not use Vyleesi. Bremelanotide's efficacy depends partly on endogenous opioid pathways, and naltrexone blocks those receptors. The interaction reduces drug effect and may cause unpredictable CNS effects [3].

Indomethacin and other NSAIDs can increase bremelanotide plasma levels by reducing renal clearance. Women taking regular NSAIDs should discuss this with their prescriber before starting Vyleesi.

What to Expect in the First Three Months

Realistic expectations matter more than optimism when starting Vyleesi. In RECONNECT, the primary endpoints were the desire domain of the Female Sexual Distress Scale-Desire (FSDS-DAO) and the FSFI desire subscale over 24 weeks. Roughly 40 percent of bremelanotide women hit the responder threshold versus about 25 percent on placebo [5]. That is a real but modest effect size. Women should assess response over at least 6 to 8 occasions of use before concluding the drug is or is not working.

Adherence beyond 3 months is lower than in trials; in real-world pharmacy data, approximately one-third of women who fill an initial prescription do not fill a second [11]. Nausea is the most cited reason. Strategies to improve retention include antiemetic pretreatment, injection-site rotation, and ensuring expectations are calibrated before the first dose.

The drug does not produce tolerance. Women who tolerate it well at first dose tend to maintain similar response over time. There is no evidence of tachyphylaxis at 12 months in available extension data.

Women who achieve partial benefit from Vyleesi but still find desire inadequate should be evaluated for concurrent hormonal contributors (particularly low testosterone or undertreated GSM) before switching to or adding another agent.